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Queens University
1.
Black, Madison.
The PD-1/PD-L1 Axis: An Immune-Mediated Mechanism of Chemoresistance in Cancer
.
Degree: Anatomy and Cell Biology, 2015, Queens University
URL: http://hdl.handle.net/1974/13145 
► The ability of tumour cells to avoid immune destruction (immune escape) and their acquired resistance to anti-cancer drugs constitute important barriers to the successful management…
(more)
▼ The ability of tumour cells to avoid immune destruction (immune escape) and their acquired resistance to anti-cancer drugs constitute important barriers to the successful management of cancer. The interaction between specific molecules on the surface of tumour cells with their corresponding receptors on immune effector cells can result in inhibition of these effector cells, consequently allowing tumour cells to evade the host’s anti-tumour immune response. The interaction of the Programmed Death Ligand 1 (PD-L1) on the surface of tumour cells with the Programmed Death-1 (PD-1) receptor on cytotoxic T lymphocytes leads to inactivation of these immune effectors, and is a specific example of an immune escape mechanism tumour cells use to avoid immune destruction. Clinically, antibodies capable of blocking the PD-1/PD-L1 interaction have demonstrated significant therapeutic benefit, and are currently being used to help bolster patients’ immune response against malignant cells in a variety of cancer types. Here we show that the PD-1/PD-L1 interaction also leads to tumour cell resistance to conventional chemotherapeutic agents. Incubation of PD-L1-expressing human and mouse tumour cells with PD-1-expressing Jurkat T cells or purified recombinant PD-1 resulted in tumour cell resistance to doxorubicin and docetaxel. Interference with the PD-1/PD-L1 interaction using blocking anti-PD-1 or anti-PD-L1 antibody or shRNA-mediated gene silencing resulted in attenuation of PD-1/PD-L1-mediated drug resistance. Moreover, inhibition of the PD-1/PD-L1 signalling axis using anti-PD-1 antibody enhanced the effect of doxorubicin chemotherapy to inhibit 4T1 tumour cell metastasis in an in vivo mouse model of mammary carcinoma. These findings indicate that blockade of the PD-1/PD-L1 axis may be a useful approach to immunosensitize and chemosensitize tumours in cancer patients and provide a rationale for the use of anti-PD-1/PD-L1 antibodies as adjuvants to chemotherapy.
Subjects/Keywords: Chemoresistance
;
PD-1/PD-L1
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APA (6th Edition):
Black, M. (2015). The PD-1/PD-L1 Axis: An Immune-Mediated Mechanism of Chemoresistance in Cancer
. (Thesis). Queens University. Retrieved from http://hdl.handle.net/1974/13145
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Black, Madison. “The PD-1/PD-L1 Axis: An Immune-Mediated Mechanism of Chemoresistance in Cancer
.” 2015. Thesis, Queens University. Accessed January 19, 2021.
http://hdl.handle.net/1974/13145.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Black, Madison. “The PD-1/PD-L1 Axis: An Immune-Mediated Mechanism of Chemoresistance in Cancer
.” 2015. Web. 19 Jan 2021.
Vancouver:
Black M. The PD-1/PD-L1 Axis: An Immune-Mediated Mechanism of Chemoresistance in Cancer
. [Internet] [Thesis]. Queens University; 2015. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1974/13145.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Black M. The PD-1/PD-L1 Axis: An Immune-Mediated Mechanism of Chemoresistance in Cancer
. [Thesis]. Queens University; 2015. Available from: http://hdl.handle.net/1974/13145
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Queens University
2.
Ling, Min.
IDENTIFICATION AND CHARACTERIZATION OF NOVEL KINASES REGULATING PROGRAMMED DEATH LIGAND-1 (PD-L1) IN IMMUNE EVASION OF TRIPLE NEGATIVE BREAST CANCER CELLS
.
Degree: Pathology and Molecular Medicine, Queens University
URL: http://hdl.handle.net/1974/28007
► The programmed death ligand-1 (PD-L1) is an immune checkpoint protein expressed on a variety of antigen-presenting cells to normalize immune system. Recently, overexpression of PD-L1…
(more)
▼ The programmed death ligand-1 (PD-L1) is an immune checkpoint protein expressed on a variety of antigen-presenting cells to normalize immune system. Recently, overexpression of PD-L1 on the surface of cancer cells has been proven to contribute to cancer immune evasion and tumor progression. Specifically, PD-L1 is found highly upregulated in Triple negative breast cancer (TNBC), a subtype of breast cancer that currently has no effective clinical therapies, allowing blockade immune checkpoint therapy a potentially effective treatment. However, the overall response rate for PD-L1 targeted immunotherapy in PD-L1 positive TNBC is less than 20%. The mechanism for this is largely unknown. It has been suggested that the levels of many other genes regulating PD-L1 may contribute to the sensitivity of cancers to immunotherapy. Therefore, there is a critical need to understand how PD-L1 is upregulated and interacts with its upstream regulators in the modulation of anti-PD-L1 immunotherapy response in TNBC. Over the past years, the literature that implicated the regulation of PD-L1 was primarily on transcription levels. For this reason, my project aims to identify post-translational modification of PD-L1 in efforts to better target it in TNBC immunotherapy.
To identify novel kinase regulators of PD-L1, we first performed a proteomic analysis of PD-L1 and identified several tyrosine kinases as novel PD-L1 interacting proteins. We provide evidence that some of these kinases (EphA3, FAK, FES, and FER) could phosphorylate PD-L1 in vitro and co-expression of FAK, FES, and FER could stabilize PD-L1 in ectopic co-expression models. Moreover, FAK inhibition, knockdown, or ectopic over-expression resulted in decreased or increased PD-L1 levels, respectively; and that inhibition of EphA2 was associated with reduced endogenous PD-L1 levels. Most significantly, knockout of FAK in BT549 TNBC cells reduces immune evasion by inhibiting cancer cells-induced T-cell apoptosis in coculture experiments. In summary, we have identified several novel kinase regulators of PD-L1 stability and immune evasion. This is a critical first step in unveiling the molecular mechanism underlying PD-L1 upregulation in TNBC immune evasion and tumorigenesis. These findings present exciting opportunities for developing a new potential target and effective combinational therapies for immunotherapy-resistant TNBC.
Subjects/Keywords: PD-L1
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APA ·
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APA (6th Edition):
Ling, M. (n.d.). IDENTIFICATION AND CHARACTERIZATION OF NOVEL KINASES REGULATING PROGRAMMED DEATH LIGAND-1 (PD-L1) IN IMMUNE EVASION OF TRIPLE NEGATIVE BREAST CANCER CELLS
. (Thesis). Queens University. Retrieved from http://hdl.handle.net/1974/28007
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ling, Min. “IDENTIFICATION AND CHARACTERIZATION OF NOVEL KINASES REGULATING PROGRAMMED DEATH LIGAND-1 (PD-L1) IN IMMUNE EVASION OF TRIPLE NEGATIVE BREAST CANCER CELLS
.” Thesis, Queens University. Accessed January 19, 2021.
http://hdl.handle.net/1974/28007.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ling, Min. “IDENTIFICATION AND CHARACTERIZATION OF NOVEL KINASES REGULATING PROGRAMMED DEATH LIGAND-1 (PD-L1) IN IMMUNE EVASION OF TRIPLE NEGATIVE BREAST CANCER CELLS
.” Web. 19 Jan 2021.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Vancouver:
Ling M. IDENTIFICATION AND CHARACTERIZATION OF NOVEL KINASES REGULATING PROGRAMMED DEATH LIGAND-1 (PD-L1) IN IMMUNE EVASION OF TRIPLE NEGATIVE BREAST CANCER CELLS
. [Internet] [Thesis]. Queens University; [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1974/28007.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.
Council of Science Editors:
Ling M. IDENTIFICATION AND CHARACTERIZATION OF NOVEL KINASES REGULATING PROGRAMMED DEATH LIGAND-1 (PD-L1) IN IMMUNE EVASION OF TRIPLE NEGATIVE BREAST CANCER CELLS
. [Thesis]. Queens University; Available from: http://hdl.handle.net/1974/28007
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.
University of Melbourne
3.
Hogg, Simon John.
BET bromodomain inhibition as combined apoptotic and immunomodulatory therapy for the treatment of MYC-driven lymphoma.
Degree: 2017, University of Melbourne
URL: http://hdl.handle.net/11343/191790
► Bromodomain and Extra-Terminal (BET) proteins are a conserved family of ‘epigenetic readers’ that bind to acetylated lysine residues on histone and non-histone proteins to modulate…
(more)
▼ Bromodomain and Extra-Terminal (BET) proteins are a conserved family of ‘epigenetic readers’ that bind to acetylated lysine residues on histone and non-histone proteins to modulate transcription. BET proteins are enriched at promoter and enhancer regions and recruit the positive transcription elongation factor b (P-TEFb) complex to activate RNA polymerase II. Anti-tumour responses elicited by BET inhibitors have been associated with the suppression of genes required for cellular proliferation and survival, including oncogenic transcription factors. Suppression of the proto-oncogene MYC was initially reported as a key mechanistic property of BET inhibitors, however more recent evidence suggests that additional target genes are mechanistically implicated.
In this thesis, the Eμ-Myc model of aggressive B-cell lymphoma was utilized to investigate the full repertoire of genes modulated by JQ1 and their functional significance in mediating therapeutic responses. JQ1 did not suppress the expression of transgenic Myc in this model, allowing the determinants of apoptosis induction to be assessed, independently of changes in Myc expression. This apoptotic response was p53-independent and associated with modulation in the ratio of pro- and antiapoptotic Bcl-2 family members to favor activation of the intrinsic mitochondrial apoptotic pathway. Therapeutic administration of JQ1 to mice bearing Eμ-Myc lymphomas led to robust clinical responses, however, universal treatment failure was observed despite ongoing therapy. Using RNA-Seq, disease progression and secondary JQ1 resistance was found to be associated with RAS pathway activation and Bcl-2 upregulation.
In addition, the efficacy of JQ1 was found to be dependent on an intact host immune system, where a 50% reduction in the survival advantage was observed upon transplantation into immune-deficient mice. Using RNA-Seq, the immune checkpoint ligand Cd274 (Pd-l1) was found to be potently suppressed by JQ1. Mechanistically, BET inhibition decreased Brd4 occupancy at the Cd274 promoter, leading to promoter-proximal pausing of RNA polymerase II, and loss of Cd274 mRNA production. Rapid epigenetic remodeling of the Cd274 locus in response to interferon gamma (IFN-γ) stimulation led to recruitment of Irf1, Brd4, RNA polymerase II, as well as increased local histone acetylation. Accordingly, BET inhibition suppressed constitutive and IFN-γ-induced PD-L1 expression in genetically diverse tumour models. Ectopic expression of PD-L1 in Eμ-Myc lymphomas was sufficient to reduce the efficacy of JQ1, demonstrating the significance of PD-L1 suppression to the observed therapeutic responses associated with BET inhibition. Finally, treatment of mice bearing Eμ-Myc lymphomas with JQ1 in combination with a checkpoint inhibitor (anti-PD-1) or immune stimulating antibody (anti-4-1BB/CD137) led to improved therapeutic responses.
The results presented herein demonstrate the importance of MYC-independent apoptotic signaling to therapeutic responses associated with BET inhibition, as well as…
Subjects/Keywords: bromodomain; epigenetics; PD-L1; cancer
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APA (6th Edition):
Hogg, S. J. (2017). BET bromodomain inhibition as combined apoptotic and immunomodulatory therapy for the treatment of MYC-driven lymphoma. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/191790
Chicago Manual of Style (16th Edition):
Hogg, Simon John. “BET bromodomain inhibition as combined apoptotic and immunomodulatory therapy for the treatment of MYC-driven lymphoma.” 2017. Doctoral Dissertation, University of Melbourne. Accessed January 19, 2021.
http://hdl.handle.net/11343/191790.
MLA Handbook (7th Edition):
Hogg, Simon John. “BET bromodomain inhibition as combined apoptotic and immunomodulatory therapy for the treatment of MYC-driven lymphoma.” 2017. Web. 19 Jan 2021.
Vancouver:
Hogg SJ. BET bromodomain inhibition as combined apoptotic and immunomodulatory therapy for the treatment of MYC-driven lymphoma. [Internet] [Doctoral dissertation]. University of Melbourne; 2017. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/11343/191790.
Council of Science Editors:
Hogg SJ. BET bromodomain inhibition as combined apoptotic and immunomodulatory therapy for the treatment of MYC-driven lymphoma. [Doctoral Dissertation]. University of Melbourne; 2017. Available from: http://hdl.handle.net/11343/191790
4.
脇田, 晃行.
REG Iα Promotes PD-L1 Expression in Esophageal Cancer Cells. : 食道扁平上皮癌細胞において REG Iαは PD-L1 の発現を誘導する.
Degree: 博士（医学）, 2017, Akita University / 秋田大学
URL: http://hdl.handle.net/10295/2884
► Regenerating gene (REG)Iα is known to contribute to carcinogenesis and to be associated with a poor prognosis in various cancers. Programmed death-1 ligand(PD-L1) is a…
(more)
▼ Regenerating gene (REG)Iα is known to contribute to carcinogenesis and to be associated with a poor prognosis in various cancers. Programmed death-1 ligand(PD-L1) is a negative regulator of T cell activation thought to play an important role in tumor evasion from host immunity.In the present study, we tested the hypothesis that the pro-survival effects of REG Iα in cancer reflect enhanced expression of PD-L1.We found that PD-L1 mRNA expression tended to correspond to REG Iα mRNA levels in esophageal squamous cancer cells, and that REG Iα expression significantly increased expression of both PD-L1 mRNA and protein in TE-5 and TE-9 squamous esophageal cancer cells transfected with REG Iα.In addition, immunohistochemical analysis of squamous cell esophageal cancer specimens revealed that the spatial distribution of PD-L1 expression corresponded to that of REG Iα. These findings suggest that REG Iα may suppress antitumor immunity by inducing PD-L1 expression.
Subjects/Keywords: PD-L1; REG Iα; esophageal cancer
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APA ·
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APA (6th Edition):
脇田, . (2017). REG Iα Promotes PD-L1 Expression in Esophageal Cancer Cells. : 食道扁平上皮癌細胞において REG Iαは PD-L1 の発現を誘導する. (Thesis). Akita University / 秋田大学. Retrieved from http://hdl.handle.net/10295/2884
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
脇田, 晃行. “REG Iα Promotes PD-L1 Expression in Esophageal Cancer Cells. : 食道扁平上皮癌細胞において REG Iαは PD-L1 の発現を誘導する.” 2017. Thesis, Akita University / 秋田大学. Accessed January 19, 2021.
http://hdl.handle.net/10295/2884.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
脇田, 晃行. “REG Iα Promotes PD-L1 Expression in Esophageal Cancer Cells. : 食道扁平上皮癌細胞において REG Iαは PD-L1 の発現を誘導する.” 2017. Web. 19 Jan 2021.
Vancouver:
脇田 . REG Iα Promotes PD-L1 Expression in Esophageal Cancer Cells. : 食道扁平上皮癌細胞において REG Iαは PD-L1 の発現を誘導する. [Internet] [Thesis]. Akita University / 秋田大学; 2017. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/10295/2884.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
脇田 . REG Iα Promotes PD-L1 Expression in Esophageal Cancer Cells. : 食道扁平上皮癌細胞において REG Iαは PD-L1 の発現を誘導する. [Thesis]. Akita University / 秋田大学; 2017. Available from: http://hdl.handle.net/10295/2884
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Toronto
5.
Nam, Junghyun.
Investigating the Immune Microenvironment in Osteosarcomas.
Degree: 2017, University of Toronto
URL: http://hdl.handle.net/1807/79276
► Osteosarcoma (OS) is a mesenchymal tumor that is the most common malignant bone tumor in children and young adults. Our objective was to identify novel…
(more)
▼ Osteosarcoma (OS) is a mesenchymal tumor that is the most common malignant bone tumor in children and young adults. Our objective was to identify novel pathways in OS that may be related to the expression of an immunosuppressive protein ‘programmed cell death ligand 1 (PD-L1)’. Using RT-qPCR, varying levels of relative PD-L1 gene expression was shown in 69 primary OS tumors. Ingenuity pathway analysis was utilized to analyze 400 significantly differentially expressed genes between the high and low PD-L1 expressing OS tumors and the elongation initiation factor 2 (EIF2) pathway was illustrated to be significantly down-regulated (p=3E-07; z-score=-2.5) and the ‘cell death of OS cells’ was predicted to be significantly activated in OS tumors with high PD-L1 expression (p=1E-04; z-score=2.53). Both IFN- and thapsigargin were utilized to observe the effects of attenuating the EIF2 pathway on PD-L1 expression. Overall, the down-regulation of the EIF2 pathway did not influence PD-L1 expression.
M.Sc.
Advisors/Committee Members: Andrulis, Irene L, Wunder, Jay S, Laboratory Medicine and Pathobiology.
Subjects/Keywords: EIF2; microenvironment; osteosarcoma; PD-L1; 0307
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APA (6th Edition):
Nam, J. (2017). Investigating the Immune Microenvironment in Osteosarcomas. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/79276
Chicago Manual of Style (16th Edition):
Nam, Junghyun. “Investigating the Immune Microenvironment in Osteosarcomas.” 2017. Masters Thesis, University of Toronto. Accessed January 19, 2021.
http://hdl.handle.net/1807/79276.
MLA Handbook (7th Edition):
Nam, Junghyun. “Investigating the Immune Microenvironment in Osteosarcomas.” 2017. Web. 19 Jan 2021.
Vancouver:
Nam J. Investigating the Immune Microenvironment in Osteosarcomas. [Internet] [Masters thesis]. University of Toronto; 2017. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1807/79276.
Council of Science Editors:
Nam J. Investigating the Immune Microenvironment in Osteosarcomas. [Masters Thesis]. University of Toronto; 2017. Available from: http://hdl.handle.net/1807/79276
University of Cambridge
6.
Chen, Sofia Yixin.
Genetic alterations defining human primary melanoma and mechanisms of immune evasion.
Degree: PhD, 2020, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/304198https://www.repository.cam.ac.uk/bitstream/1810/304198/3/6b339e05-7c50-455c-89b1-85cf227a3364_confirmations.txt
;
https://www.repository.cam.ac.uk/bitstream/1810/304198/4/license.txt
;
https://www.repository.cam.ac.uk/bitstream/1810/304198/5/6b339e05-7c50-455c-89b1-85cf227a3364.zip
► The somatic mutations found in melanomas reflect the biological processes that govern tumour development. They also help shape how tumours evolve and escape immune regulation.…
(more)
▼ The somatic mutations found in melanomas reflect the biological processes that govern tumour development. They also help shape how tumours evolve and escape immune regulation. Studying these changes can therefore help to refine our understanding of melanoma progression with the added potential to offer new perspectives for disease management.
Most prior melanoma sequencing studies have focused on advanced disease. Thus, somatic alterations that influence the behaviour of early-stage tumours have not been fully explored. Consequently, in this thesis I study a collection of 524 primary melanomas on which extensive clinical data have been collected for almost two decades. I describe the mutational landscape of these tumours including driver genes, new recurrent variants, mutually exclusive genetic interactions and copy number alterations. I discuss and associate these features with aspects of tumour pathology, sun exposure, immunogenicity and patient outcomes. To identify genes required for melanoma survival, I intersect my genomic analysis with a dataset of CRISPR-Cas9 dropout screens and discover a melanoma-associated genetic vulnerability mediated by Interferon Regulatory Factor 4 (IRF4). I then begin to experimentally validate and explore the biological pathway by which IRF4 may function in the context of melanoma.
Checkpoint inhibitors have revolutionised melanoma care, yet only a minority of patients respond to these treatments and our comprehension of the mechanisms governing PD-L1 expression on melanoma cells is still limited. In the second part of this thesis, I examine the regulation of the key checkpoint receptor PD-L1, which is often upregulated in melanoma to facilitate tumour escape. To improve our understanding of the processes controlling PD-L1 expression, and how the PD-1/PD-L1 axis can be targeted to overcome immune evasion, I employ a genome-wide CRISPR-Cas9 screening approach. I identify genes which elicit downregulation of PD-L1 when disrupted in melanoma cells, capturing several central processes including basal transcription, N-linked glycosylation and intracellular transport. A second extensive screen in eight cancer cell lines of melanoma, bladder and lung cancer origin validate these findings and link novel candidate genes, including Sphingolipid Transporter 1 (SPNS1), to the control of PD-L1 cell surface expression. Additional work is required to further validate and understand the regulation of PD-L1 through SPNS1, as well as its contribution to immune surveillance.
In summary, I present the first comprehensive evaluation into the somatic alteration landscape of primary melanomas, gaining insight into the molecular architecture of these tumours. Additionally, I introduce novel genes and processes regulating PD-L1 gene transcription, processing and presentation on the cell surface. Collectively, these results improve our understanding of the genetic processes that govern primary melanomas, as well as providing valuable insights into the mechanism of PD-L1 regulation.
Subjects/Keywords: melanoma; genetic; alterations; immune; PD-L1
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APA ·
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APA (6th Edition):
Chen, S. Y. (2020). Genetic alterations defining human primary melanoma and mechanisms of immune evasion. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/304198https://www.repository.cam.ac.uk/bitstream/1810/304198/3/6b339e05-7c50-455c-89b1-85cf227a3364_confirmations.txt ; https://www.repository.cam.ac.uk/bitstream/1810/304198/4/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/304198/5/6b339e05-7c50-455c-89b1-85cf227a3364.zip
Chicago Manual of Style (16th Edition):
Chen, Sofia Yixin. “Genetic alterations defining human primary melanoma and mechanisms of immune evasion.” 2020. Doctoral Dissertation, University of Cambridge. Accessed January 19, 2021.
https://www.repository.cam.ac.uk/handle/1810/304198https://www.repository.cam.ac.uk/bitstream/1810/304198/3/6b339e05-7c50-455c-89b1-85cf227a3364_confirmations.txt ; https://www.repository.cam.ac.uk/bitstream/1810/304198/4/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/304198/5/6b339e05-7c50-455c-89b1-85cf227a3364.zip.
MLA Handbook (7th Edition):
Chen, Sofia Yixin. “Genetic alterations defining human primary melanoma and mechanisms of immune evasion.” 2020. Web. 19 Jan 2021.
Vancouver:
Chen SY. Genetic alterations defining human primary melanoma and mechanisms of immune evasion. [Internet] [Doctoral dissertation]. University of Cambridge; 2020. [cited 2021 Jan 19].
Available from: https://www.repository.cam.ac.uk/handle/1810/304198https://www.repository.cam.ac.uk/bitstream/1810/304198/3/6b339e05-7c50-455c-89b1-85cf227a3364_confirmations.txt ; https://www.repository.cam.ac.uk/bitstream/1810/304198/4/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/304198/5/6b339e05-7c50-455c-89b1-85cf227a3364.zip.
Council of Science Editors:
Chen SY. Genetic alterations defining human primary melanoma and mechanisms of immune evasion. [Doctoral Dissertation]. University of Cambridge; 2020. Available from: https://www.repository.cam.ac.uk/handle/1810/304198https://www.repository.cam.ac.uk/bitstream/1810/304198/3/6b339e05-7c50-455c-89b1-85cf227a3364_confirmations.txt ; https://www.repository.cam.ac.uk/bitstream/1810/304198/4/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/304198/5/6b339e05-7c50-455c-89b1-85cf227a3364.zip
University of New South Wales
7.
Voli, Florida.
Tumour copper levels regulate PD-L1 driven immune evasion.
Degree: Children's Cancer Institute Australia for Medical Research, 2019, University of New South Wales
URL: http://handle.unsw.edu.au/1959.4/64905
► Cancer immune evasion is recognised as a central hallmark of tumour development. One mechanism that cancer cells use to protect themselves from anti-tumour immune responses…
(more)
▼ Cancer immune evasion is recognised as a central hallmark of tumour development. One mechanism that cancer cells use to protect themselves from anti-tumour immune responses is the over-expression of Programmed Death Ligand 1 (
PD-
L1). The immune checkpoint protein Programmed Death receptor 1 (
PD-1) expressed by lymphocytes negatively regulates T-cellseffector functions against target cells, including tumour cells. Several therapeutic monoclonal antibodies targeting
PD-
L1/
PD-1 have been approved by the FDA for adult melanoma and lung cancer. However, their efficacy is limited by acquired resistance and immune-related adverse events in many patients. Additionally, the regulation of
PD-
L1 expression on tumour cells is still poorly understood.Copper transporter 1 (CTR-1) and copper levels are elevated in tumours and the use of copper targeting agents is currently under intense investigations. It has been also reported that copper plays a major role in the immune system, but its activity is unclear. In this study, we demonstrated for the first time that copper plays a key role in the expression of
PD-
L1 in cancer cells. Tissue microarrays from neuroblastoma and glioblastoma patients showed a significant correlation between CTR-1 and
PD-
L1 expression (p<0.0001 and p=0.006 respectively). Deep analysis of the TCGA database showed that CTR-1 and
PD-
L1 association also occurs across many cancer types characterised by high copper levels, but not in the corresponding normal tissues. In vitro experiments showed that copper supplementation enhanced
PD-
L1 expression at mRNA and protein levels in cancer cells. Consistently, Dextran-Catechin (DC) and TEPA, copper-lowering drugs, were able to down-regulate
PD-
L1 expression in cancer cells, both post-transcriptionally by inhibiting EGFR-phosphorylation and promoting ubiquitin-mediated
PD-
L1 degradation and transcriptionally by reducing STAT signalling pathway. In vivo studies showed that copper-lowering drugs slowed tumour growth and improved mice survival, by down-regulating
PD-
L1 expression, which in turn caused a significantly increase in number of tumour-infiltrating CD8+ T cells and natural killer cells.This study reveals an important role for copper in regulating
PD-
L1 expression and it raises the potential of repurposing copper-lowering drugs to enhance immune checkpoint blockade. This novel therapeutic approach could target a wide spectrum of copper-dependent cancers.
Advisors/Committee Members: Vittorio, Orazio, Women's & Children's Health, Faculty of Medicine, UNSW, Kavallaris, Maria, Women's & Children's Health, Faculty of Medicine, UNSW.
Subjects/Keywords: PD-L1; Copper; Immune evasion; Cancer
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APA (6th Edition):
Voli, F. (2019). Tumour copper levels regulate PD-L1 driven immune evasion. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/64905
Chicago Manual of Style (16th Edition):
Voli, Florida. “Tumour copper levels regulate PD-L1 driven immune evasion.” 2019. Doctoral Dissertation, University of New South Wales. Accessed January 19, 2021.
http://handle.unsw.edu.au/1959.4/64905.
MLA Handbook (7th Edition):
Voli, Florida. “Tumour copper levels regulate PD-L1 driven immune evasion.” 2019. Web. 19 Jan 2021.
Vancouver:
Voli F. Tumour copper levels regulate PD-L1 driven immune evasion. [Internet] [Doctoral dissertation]. University of New South Wales; 2019. [cited 2021 Jan 19].
Available from: http://handle.unsw.edu.au/1959.4/64905.
Council of Science Editors:
Voli F. Tumour copper levels regulate PD-L1 driven immune evasion. [Doctoral Dissertation]. University of New South Wales; 2019. Available from: http://handle.unsw.edu.au/1959.4/64905
University of New South Wales
8.
Wang, Yiming.
Investigation of GS1 and GS2 C. concisus adaptation in the human gastrointestinal tract and their effects on PD-L1 expression in human intestinal epithelial cells.
Degree: Biotechnology & Biomolecular Sciences, 2018, University of New South Wales
URL: http://handle.unsw.edu.au/1959.4/60214
;
https://unsworks.unsw.edu.au/fapi/datastream/unsworks:51079/SOURCE02?view=true
► Campylobacter concisusis a Gram-negative bacterium with a singular polar flagellum and curved morphology that enables it to traverse the mucus layer and directly contact the…
(more)
▼ Campylobacter concisusis a Gram-negative bacterium with a singular polar flagellum and curved morphology that enables it to traverse the mucus layer and directly contact the intestinal epithelium, providing the opportunity to trigger intestinal inflammation and facilitate the progression of inflammatory diseases to cancer. This thesis reports novel findings regarding the adaptation of different genomospecies of C. concisus to the human gastrointestinal tract and the potential for C. concisus to affect the
PD-1 and
PD-
L1 pathway and thus the development of inflammatory-driven cancer.C. concisus was previously reported to be associated with inflammatory bowel disease (IBD). It has two genomospecies (GS) that carry distinct and specific genes, suggesting they may have different pathogenic potentials. Previous studies have found that GS2 C. concisus strains are invasive to intestinal epithelial cells, suggesting that they may contribute to the initiation of IBD. However, no clinical studies to date have demonstrated GS2 strains to be more associated with IBD. In Chapter 2, the colonization of the human gastrointestinal tract by GS1 and GS2 C. concisus is systematically examined in patients with IBD and in healthy controls. This chapter provides novel information regarding the adaptation of different genomospecies of C. concisus to the human gastrointestinal tract. Two new PCR methods were developed and validated for detecting and quantifying C. concisus strains, based on polymorphisms of the 23S rRNA gene. These PCR methods were used to evaluate GS1 and GS2 C. concisus prevalence in 56 oral and enteric samples. Quantitative PCR showed significantly higher level of GS2 C. concisus than GS1 C. concisus in samples collected from the upper and lower gastrointestinal tracts of both patients with IBD and healthy controls, indicating that GS2 C. concisus is better adapted to the human gastrointestinal tract. A meta-analysis of the compositions of GS1 and GS2 C. concisus strains isolated in previous studies was also conducted, and showed similar findings except that a significantly lower number of GS2 strains were isolated from faecal samples of healthy individuals; this suggests a potential difference between healthy controls and patients with gastrointestinal diseases in either colonizing strains or the enteric environment. Overall, the human gastrointestinal tract harbours a complex community of bacteria, some of which are pathogens capable of establishing chronic infections. These microbes may be involved in the development of inflammation-driven cancer. The immune system uses various effector cells and molecules to control and eradicate infectious agents and cancer cells. In particular, cytotoxic T cells (CTL) are major effector cells in anti-tumour immune responses. However, the functions of these effector cells can be inhibited by immune checkpoint proteins and molecules in tumour environments; this inhibition contributes to cancer cell immune evasion. Accordingly, the blockade of immune checkpoint proteins and molecules,…
Advisors/Committee Members: Zhang, Li, Biotechnology & Biomolecular Sciences, Faculty of Science, UNSW.
Subjects/Keywords: PD-L1; Campylobacter concisus; Inflammatory bowel disease
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APA ·
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MLA ·
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APA (6th Edition):
Wang, Y. (2018). Investigation of GS1 and GS2 C. concisus adaptation in the human gastrointestinal tract and their effects on PD-L1 expression in human intestinal epithelial cells. (Masters Thesis). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/60214 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:51079/SOURCE02?view=true
Chicago Manual of Style (16th Edition):
Wang, Yiming. “Investigation of GS1 and GS2 C. concisus adaptation in the human gastrointestinal tract and their effects on PD-L1 expression in human intestinal epithelial cells.” 2018. Masters Thesis, University of New South Wales. Accessed January 19, 2021.
http://handle.unsw.edu.au/1959.4/60214 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:51079/SOURCE02?view=true.
MLA Handbook (7th Edition):
Wang, Yiming. “Investigation of GS1 and GS2 C. concisus adaptation in the human gastrointestinal tract and their effects on PD-L1 expression in human intestinal epithelial cells.” 2018. Web. 19 Jan 2021.
Vancouver:
Wang Y. Investigation of GS1 and GS2 C. concisus adaptation in the human gastrointestinal tract and their effects on PD-L1 expression in human intestinal epithelial cells. [Internet] [Masters thesis]. University of New South Wales; 2018. [cited 2021 Jan 19].
Available from: http://handle.unsw.edu.au/1959.4/60214 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:51079/SOURCE02?view=true.
Council of Science Editors:
Wang Y. Investigation of GS1 and GS2 C. concisus adaptation in the human gastrointestinal tract and their effects on PD-L1 expression in human intestinal epithelial cells. [Masters Thesis]. University of New South Wales; 2018. Available from: http://handle.unsw.edu.au/1959.4/60214 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:51079/SOURCE02?view=true
University of Vienna
9.
Plangger, Adelina Sophia.
Lung cancer: chemosensitivity and PD-L1 expression of primary non-small cell lung (NSCLC) cancer cell lines.
Degree: 2019, University of Vienna
URL: http://othes.univie.ac.at/60284/
► Der nicht-kleinzellige Lungenkrebs (NSCLC) macht zirka 85% der Lungenkrebsarten aus. Die klassische Therapiemöglichkeit zur Behandlung von Lungenkrebs besteht aus platinbasierten Medikamenten (Cisplatin oder Carboplatin) in…
(more)
▼ Der nicht-kleinzellige Lungenkrebs (NSCLC) macht zirka 85% der Lungenkrebsarten aus. Die klassische Therapiemöglichkeit zur Behandlung von Lungenkrebs besteht aus platinbasierten Medikamenten (Cisplatin oder Carboplatin) in Kombination mit Docetaxel, Etoposid oder Pemetrexed, aber bisher beträgt die 5-Jahres-Überlebensrate trotz dieser Kombination nur rund 20%. Patienten, die eine Mutation in einer „Treiber Kinase“ wie EGFR, ALK oder ROS1 haben, sind empfänglich für gezielte Therapien mit spezifischen Tyrosin Kinase Inhibitoren (TKIs) was zu einem verbesserten Überleben mit mehr als 5 Jahren führen kann. Dennoch müssen Patienten, die unter TKI Behandlung einen Progress erleiden, mit einer zytotoxischen Chemotherapie behandelt werden. Chemoresistenz wird oft bei Patienten beobachtet, die mit platinbasierten Medikamenten behandelt wurden. In dieser Arbeit wurde die Sensitivität von PD-L1 negativen primären NSCLC und permanenten Lungenkrebs Linien mittels Proliferationsassays, Immunofluoreszenztests, Polymerasekettenreaktion und Westernblot Arrays untersucht. Die Ergebnisse der Cisplatin Zytotoxizitätstests zeigen, dass die meisten pleuralen NSCLC Linien IC50 Werte aufweisen, die nahe bei 3 µg/ml liegen. Dieser Wert entspricht in etwa der klinischen Spitzenplasmakonzentration und indiziert deshalb Chemoresistenz der Zellen. Die NSCLC zu SCLC transformierten Pleurazelllinien BH659 und BH686 erwiesen sich als hoch chemosensitiv. Um die zytotoxische Wirkung von Cisplatin zu verstärken, wurden Kombinationen mit dem Chk-1/2-Inhibitor AZD-7762, dem HSP90-Inhibitor STA9090, dem Nrf-2-Inhibitor ML385, dem Multitargetinhibitor Niclosamid und dem Signaltransduktionshemmer Pristimerin durchgeführt. AZD-7762, das eine Initiation der Reparatur der DNA Schäden inhibiert, und Multitarget Niclosamid ergaben die höchste Rate synergistischer Zytotoxizität in Kombination mit Cisplatin, während Versuche mit mehreren Krebslinien und anderen Modulatoren negative Ergebnisse lieferten. Um die Zytotoxizitätstests auf ein repräsentativeres in vivo-ähnliches Tumormodell auszudehnen, wurden 3D-Aggregate getestet, die in mit Agarose beschichteten Kulturflaschen kultiviert wurden. Die meisten Linien zeigten eine erhöhte Resistenz gegen Cisplatin als 3D-Aggregate und mit Ausnahme von Niclosamid Kombinationen waren die Modulatoren gegenüber solchen Zellaggregaten weniger wirksam. Mittels Westernblot Arrays wurden die spezifischen Phosphorylierungsstellen von Chk-2, ERK1/2, AKT1/2/3, c-Jun, STAT3 und die Proteinexpression von HSP60 untersucht. Chk-2, c-Jun, STAT3 und HSP60 zeigten die häufigsten Anstiege der Phosphorylierung oder Proteinexpression als Reaktion auf die Vorbehandlung der Zellen mit Cisplatin. Die Cisplatin-induzierte Phosphorylierung wurde in Zelllinien verstärkt, die zu Beginn basale Phosphorylierungsgrade aufwiesen. Die transformierten Zelllinien BH659 und BH686 zeigten eine geringe und gleichmäßige Erhöhung des Phosphorylierungsstatus derselben Proteine. Ihre tatsächliche Transformation in einen SCLC-Phänotyp wurde durch den Nachweis…
Subjects/Keywords: 42.13 Molekularbiologie; Lungenkrebs / Chemoresistenz / Cisplatin / PD-L1; Lung cancer / chemoresistance / cisplatin / PD-L1
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APA ·
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CSE |
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APA (6th Edition):
Plangger, A. S. (2019). Lung cancer: chemosensitivity and PD-L1 expression of primary non-small cell lung (NSCLC) cancer cell lines. (Thesis). University of Vienna. Retrieved from http://othes.univie.ac.at/60284/
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Plangger, Adelina Sophia. “Lung cancer: chemosensitivity and PD-L1 expression of primary non-small cell lung (NSCLC) cancer cell lines.” 2019. Thesis, University of Vienna. Accessed January 19, 2021.
http://othes.univie.ac.at/60284/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Plangger, Adelina Sophia. “Lung cancer: chemosensitivity and PD-L1 expression of primary non-small cell lung (NSCLC) cancer cell lines.” 2019. Web. 19 Jan 2021.
Vancouver:
Plangger AS. Lung cancer: chemosensitivity and PD-L1 expression of primary non-small cell lung (NSCLC) cancer cell lines. [Internet] [Thesis]. University of Vienna; 2019. [cited 2021 Jan 19].
Available from: http://othes.univie.ac.at/60284/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Plangger AS. Lung cancer: chemosensitivity and PD-L1 expression of primary non-small cell lung (NSCLC) cancer cell lines. [Thesis]. University of Vienna; 2019. Available from: http://othes.univie.ac.at/60284/
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
10.
Yazbeck, Nathalie.
Contrôle de l’immunité antitumorale par la signalisation de SQSTM1 : Control of antitumor immunity by the SQSTM1 dependent signaling.
Degree: Docteur es, Interractions moléculaires et cellulaires, 2018, Université Côte d'Azur (ComUE)
URL: http://www.theses.fr/2018AZUR4072
► La dernière décennie a connu une révolution dans le traitement du cancer en s'éloignant des médicaments conventionnels qui ciblent directement la tumeur (comme les chimiothérapies…
(more)
▼ La dernière décennie a connu une révolution dans le traitement du cancer en s'éloignant des médicaments conventionnels qui ciblent directement la tumeur (comme les chimiothérapies et les thérapies moléculaires ciblées) au profit des immunothérapies, et en particulier les inhibiteurs des "checkpoint" immunitaires. Ces immunothérapies libèrent sélectivement le système immunitaire de l'hôte contre la tumeur et ont démontré une rémission durable sans précédent chez des patients atteints de cancers que l'on croyait incurables, comme le mélanome métastatique, le carcinome rénal métastatique et les stades avancés du cancer du poumon non à petites cellules. Cependant, plus de la moitié des patients ne répondent pas à ces traitements, et sont donc contraints à recevoir d’autres traitements potentiellement toxiques et coûteux. Face aux résultats prometteurs des immunothérapies anti‐PD1/PD‐L1, la recherche de nouvelles cibles/marqueurs moléculaires permettant d'améliorer l'efficacité et de permettre un traitement personnalisé s'est intensifiée. Nos travaux portent sur l’étude de la protéine Sequestosome 1 (SQSTM1/p62) qui est un substrat de l'autophagie sélective et une plateforme de signalisation impliquée dans l’agressivité tumorale. Nous mettons en évidence l’implication de SQSTM1/p62 dans l'inflammation tumorale et dans l’évasion immunitaire et ceci grâce à la stabilisation du messager de PD‐L1. Nous observons que la surexpression tumorale de SQSTM1/p62 caractérise les tumeurs infiltrées et immunosuppressives qui répondent le mieux aux anti‐PD1/PD‐L1. Ainsi, nous proposons SQSTM1/p62 en tant que biomarqueur potentiel et cible thérapeutique pour améliorer la stratification des patients susceptibles de répondre aux immunothérapies.
The past decade has witnessed a new revolution in cancer treatment by shifting away from the conventional drugs that directly target the tumor (such as chemotherapies and molecular targeted therapies) towards immune‐based therapies, and in particular the so‐called immune checkpoint inhibitors. These immunotherapies selectively release the host immune system against the tumor and have shown unprecedented durable remission for patients with cancers that were thought incurable such as metastatic melanoma, metastatic renal cell carcinoma and late stages of non‐small cell lung cancer. However, more than half of the patients fail to respond to these treatments and are therefore forced to receive other potentially toxic and costly treatments. In this era of promising anti‐PD1/PD‐L1 immunotherapies, the quest for reliable molecular markers/therapeutic targets that would enhance the effectiveness and allow a personalized adaptation of the treatments has intensified. In our work we focus on the scaffold protein and autophagy adaptor Sequestosome 1 (SQSTM1/p62), and we show that it is required for tumor inflammation and immune evasion. We find that SQSTM1/p62 tumor overexpression characterizes infiltrated and immunosuppressive tumors and predicts for response to anti‐PD1/PD‐L1 therapies. Thus, we propose…
Advisors/Committee Members: Mograbi, Baharia (thesis director), Hofman, Paul (thesis director).
Subjects/Keywords: Immunothérapies; PD1/PD‐L1; Biomarqueurs; Sequestosome 1; Immunotherapies; PD1/PD‐L1; Biomarker; Sequestosome 1
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APA ·
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MLA ·
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CSE |
Export
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Manager
APA (6th Edition):
Yazbeck, N. (2018). Contrôle de l’immunité antitumorale par la signalisation de SQSTM1 : Control of antitumor immunity by the SQSTM1 dependent signaling. (Doctoral Dissertation). Université Côte d'Azur (ComUE). Retrieved from http://www.theses.fr/2018AZUR4072
Chicago Manual of Style (16th Edition):
Yazbeck, Nathalie. “Contrôle de l’immunité antitumorale par la signalisation de SQSTM1 : Control of antitumor immunity by the SQSTM1 dependent signaling.” 2018. Doctoral Dissertation, Université Côte d'Azur (ComUE). Accessed January 19, 2021.
http://www.theses.fr/2018AZUR4072.
MLA Handbook (7th Edition):
Yazbeck, Nathalie. “Contrôle de l’immunité antitumorale par la signalisation de SQSTM1 : Control of antitumor immunity by the SQSTM1 dependent signaling.” 2018. Web. 19 Jan 2021.
Vancouver:
Yazbeck N. Contrôle de l’immunité antitumorale par la signalisation de SQSTM1 : Control of antitumor immunity by the SQSTM1 dependent signaling. [Internet] [Doctoral dissertation]. Université Côte d'Azur (ComUE); 2018. [cited 2021 Jan 19].
Available from: http://www.theses.fr/2018AZUR4072.
Council of Science Editors:
Yazbeck N. Contrôle de l’immunité antitumorale par la signalisation de SQSTM1 : Control of antitumor immunity by the SQSTM1 dependent signaling. [Doctoral Dissertation]. Université Côte d'Azur (ComUE); 2018. Available from: http://www.theses.fr/2018AZUR4072
Harvard University
11.
Talat, Hammad.
Combination Immunotherapy for Glioblastoma Multiforme With the Combination of GVAX and PD-1 Blockade, Using Anti-PD1 Antibody.
Degree: ALM, 2018, Harvard University
URL: http://nrs.harvard.edu/urn-3:HUL.InstRepos:42004052
► Glioblastoma Multiforme (GBM), also known as grade IV astrocytoma, is generally found in the cerebral hemispheres but can be found anywhere else in the brain…
(more)
▼ Glioblastoma Multiforme (GBM), also known as grade IV astrocytoma, is generally found in the cerebral hemispheres but can be found anywhere else in the brain or the spinal cord. Even after surgery and chemotherapy, GBM has a high rate of recurrence. Median survival after diagnosis is 12 months, with less than 3 to 5% people surviving greater than 5 years. Without treatment, average survival is about 3 months. Immune checkpoint inhibition is a recent addition to the regimen of treatment of cancers and has shown some promising results in Melanoma and lung cancer.
The primary research goal of this thesis was to study if treatment with a combination of GVAX and PD-1 blockade leads to improved survival in comparison to PD-1 treatment alone in a mouse glioma model. If a combination treatment of GVAX and PD-1 leads to improved survival as compared to PD-1 treatment alone, a secondary goal of my research was to identify the underlying immune mechanisms that were responsible for this survival advantage. Finally, a third goal of my research was to examine survival advantage, if any, from treatment with GVAX and PD-1 can be enhanced further with the addition of a second immune checkpoint molecule.
Data from this study is presented which shows that combination immunotherapy with GVAX and Anti-PD1 does provide survival advantage by increasing tumor infiltration of Cd8+ T-cells into the tumor and by increasing Cd8+ T-cells to Treg cell ratio. The survival advantages conferred by the combination of GVAX and Anti-PD1 was further enhanced by the addition of second immune checkpoint molecule OX40.Triple combination treated mice also developed immune memory towards the tumor and long-term survivors rejected a tumor challenge with three times more cells than the initial tumor challenge. These results confirm the initial hypothesis that combination immunotherapy with GVAX and immune checkpoint molecules can be an efficacious treatment for patients with GBM.
Biology
Advisors/Committee Members: Curry, William T. (committee member), Morris, James (committee member).
Subjects/Keywords: Glioma; Immunotherapy; GVAX; PD-1; PD-L1; OX-40; Glioblastoma
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APA (6th Edition):
Talat, H. (2018). Combination Immunotherapy for Glioblastoma Multiforme With the Combination of GVAX and PD-1 Blockade, Using Anti-PD1 Antibody. (Masters Thesis). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:42004052
Chicago Manual of Style (16th Edition):
Talat, Hammad. “Combination Immunotherapy for Glioblastoma Multiforme With the Combination of GVAX and PD-1 Blockade, Using Anti-PD1 Antibody.” 2018. Masters Thesis, Harvard University. Accessed January 19, 2021.
http://nrs.harvard.edu/urn-3:HUL.InstRepos:42004052.
MLA Handbook (7th Edition):
Talat, Hammad. “Combination Immunotherapy for Glioblastoma Multiforme With the Combination of GVAX and PD-1 Blockade, Using Anti-PD1 Antibody.” 2018. Web. 19 Jan 2021.
Vancouver:
Talat H. Combination Immunotherapy for Glioblastoma Multiforme With the Combination of GVAX and PD-1 Blockade, Using Anti-PD1 Antibody. [Internet] [Masters thesis]. Harvard University; 2018. [cited 2021 Jan 19].
Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:42004052.
Council of Science Editors:
Talat H. Combination Immunotherapy for Glioblastoma Multiforme With the Combination of GVAX and PD-1 Blockade, Using Anti-PD1 Antibody. [Masters Thesis]. Harvard University; 2018. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:42004052
12.
Fournel, Ludovic.
Influence Du Cisplatine sur l'expression du Check-Point Immunitaire PD-1/PD-L1 Dans Le Cancer Broncho-Pulmonaire Non A Petites Cellules : impact of Cisplatin on the Expression of Immune Check-Point PD-1/PD-L1 in Non Small Cell Lung Carcinoma.
Degree: Docteur es, Sciences de la vie et de la santé, 2020, université Paris-Saclay
URL: http://www.theses.fr/2020UPASS077
► Malgré les nombreux progrés réalisés ces dernières années dans la prise en charge thérapeutique du cancer broncho-pulmonaire, cette pathologie reste la première cause de décès…
(more)
▼ Malgré les nombreux progrés réalisés ces dernières années dans la prise en charge thérapeutique du cancer broncho-pulmonaire, cette pathologie reste la première cause de décès lié au cancer dans le monde. L’enjeu majeur pour cette maladie est donc de développer de nouveaux traitements et d’optimiser l’utilisation des drogues existantes, en particulier les sels de platine. Les protocoles combinant des inhibiteurs de points de contrôle immunitaire avec des sels de platine est actuellement en plein essor malgré un certain manque en études précliniques. Dans ce travail, j’ai cherché à évaluer l'impact du cisplatine sur l'expression de PD-L1 en analysant des patients ayant reçu une chimiothérapie néo-adjuvante à base de cisplatine. Le traitement d'induction augmentait considérablement le marquage PD-L1 des cellules tumorales et immunitaires du microenvironnement. Vingt-deux patients présentaient une variation positive du pourcentage de cellules tumorales PD-L1+ après chimiothérapie néoadjuvante; dont 9 (23,1%) passant de <50% à ≥50% des cellules tumorales marquées. Nous avons également confirmé la régulation positive de PD-L1 par le cisplatine, tant au niveau de l'ARNm qu’au niveau protéique, in-vitro et in-vivo sur des souris nude et des souris immunocompétentes greffées par des tumeurs expérimentales issues de lignées cellulaires de cancer du poumon A549, LNM-R ou LLC1. L’up-régulation de PD-L1 par le cisplatine fait intervenir la voie de signalisation PI3K/AKT. De plus, l'administration combinée d'anticorps anti-PD-L1 (3 mg / kg) et de cisplatine (1 mg / kg) à des souris portant un carcinome pulmonaire réduisait significativement la croissance tumorale par rapport aux traitements en monothérapie et par rapport aux contrôles. Le cisplatine augmente donc précocément et durablement l'expression de PD-L1 et pourrait donc agir de manière synergique avec un blocage de PD-1 / PD-L1 pour améliorer la réponse tumorale aux traitements. En parallèle, nous avons pu développer une thérapie ciblée anti-neurotensine permettant de bloquer ses effets paracrines stimulants la prolifération, la croissance, et les capacités d’invasion des cellules de tumeurs pulmonaires. Les anticorps anti-neurotensine amélioraient également la sensibilité au cisplatine de tumeurs préalablement résistantes par des mécanismes qui impliquent probablement l’augmentation de l’influx et la diminution de l’efflux de platine au niveau de sa cible intra-nucléaire qu’est l’ADN. L’ensemble de ces résultats apportent du rationnel à la réalisation d’essais cliniques impliquant le cisplatine et visant par différents biais à améliorer l’efficacité de traitements systémiques de cancers broncho-pulmonaires non à petites cellules.
Despite many advances in the recent years in the therapeutic management of bronchopulmonary cancer, it remains the leading cause of death linked to cancer in the world. The major challenge for this disease is therefore to develop new treatments and optimize the use of existing drugs, in particular platinum salts. The number of clinical…
Advisors/Committee Members: Forgez, Patricia (thesis director), Alifano, Marco (thesis director).
Subjects/Keywords: Carcinome broncho-Pulmonaire; Pd1/pd-L1; Immunothérapie; Cisplatine; Neurotensine; Lung carcinoma; Pd-1/pd-L1; Immune therapy; Cisplatin; Neurotensin
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APA ·
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CSE |
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Manager
APA (6th Edition):
Fournel, L. (2020). Influence Du Cisplatine sur l'expression du Check-Point Immunitaire PD-1/PD-L1 Dans Le Cancer Broncho-Pulmonaire Non A Petites Cellules : impact of Cisplatin on the Expression of Immune Check-Point PD-1/PD-L1 in Non Small Cell Lung Carcinoma. (Doctoral Dissertation). université Paris-Saclay. Retrieved from http://www.theses.fr/2020UPASS077
Chicago Manual of Style (16th Edition):
Fournel, Ludovic. “Influence Du Cisplatine sur l'expression du Check-Point Immunitaire PD-1/PD-L1 Dans Le Cancer Broncho-Pulmonaire Non A Petites Cellules : impact of Cisplatin on the Expression of Immune Check-Point PD-1/PD-L1 in Non Small Cell Lung Carcinoma.” 2020. Doctoral Dissertation, université Paris-Saclay. Accessed January 19, 2021.
http://www.theses.fr/2020UPASS077.
MLA Handbook (7th Edition):
Fournel, Ludovic. “Influence Du Cisplatine sur l'expression du Check-Point Immunitaire PD-1/PD-L1 Dans Le Cancer Broncho-Pulmonaire Non A Petites Cellules : impact of Cisplatin on the Expression of Immune Check-Point PD-1/PD-L1 in Non Small Cell Lung Carcinoma.” 2020. Web. 19 Jan 2021.
Vancouver:
Fournel L. Influence Du Cisplatine sur l'expression du Check-Point Immunitaire PD-1/PD-L1 Dans Le Cancer Broncho-Pulmonaire Non A Petites Cellules : impact of Cisplatin on the Expression of Immune Check-Point PD-1/PD-L1 in Non Small Cell Lung Carcinoma. [Internet] [Doctoral dissertation]. université Paris-Saclay; 2020. [cited 2021 Jan 19].
Available from: http://www.theses.fr/2020UPASS077.
Council of Science Editors:
Fournel L. Influence Du Cisplatine sur l'expression du Check-Point Immunitaire PD-1/PD-L1 Dans Le Cancer Broncho-Pulmonaire Non A Petites Cellules : impact of Cisplatin on the Expression of Immune Check-Point PD-1/PD-L1 in Non Small Cell Lung Carcinoma. [Doctoral Dissertation]. université Paris-Saclay; 2020. Available from: http://www.theses.fr/2020UPASS077
Karlstad University
13.
Härdin, Jonas.
Cutibacterium acnes inverkan på makrofagers produktion av PD-L1.
Degree: Environmental and Life Sciences (from 2013), 2020, Karlstad University
URL: http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-78770
► Prostatacancer är den vanligaste cancerformen hos män i Sverige, och det är även den cancerform som flest män dör utav. Detta till trots så…
(more)
▼ Prostatacancer är den vanligaste cancerformen hos män i Sverige, och det är även den cancerform som flest män dör utav. Detta till trots så är mekanismerna bakom canceretiologin till stor del okända. Uppskattningsvis 20% av alla canceruppkomster i människor tros vara länkade till infektioner från patogener och de inflammationer som de orsakar. Tidigare studier har visat indikationer på att kronisk inflammation av prostatan kan hjälpa tumörer att undvika immunförsvaret. Bakterien Cutibacterium acnes förekommer i stor utsträckning i prostatavävnad hos patienter som lider av prostatacancer vilket kan peka på en länk mellan mikroorganismen och cancerformen. Tumörassocierade makrofager kan producera immunhämmande proteiner, däribland liganden PD-L1, ett protein som kan hjälpa tumörcellerna att undgå immunförsvaret. Studien ämnade därför att undersöka huruvida makrofager som infekterats med typ I eller typ II C. acnes producerar en högre mängd av PD-L1 än obehandlade makrofager och i detta syfte utfördes ett ELISA-test som bestämde koncentrationen av PD-L1 i odlingsmediumet. Genom en statistisk analys konstaterades att makrofager som infekterats med bakterien ökade produktionen av PD-L1 jämfört med obehandlade makrofager. Resultatet av studien visar indikationer på att C. acnes kan spela en roll i spridningen av tumörceller i kroppen, dock krävs vidare studier för att bekräfta hypotesen.
Prostate cancer is the most common form of cancer among men in Sweden, and the form of cancer that most men die from. In spite of this, the mechanisms behind the etiology of the cancer are largely unknown. Approximately 20% of all cancer etiologies are believed to be linked to infection by pathogens, and the inflammatory response they cause within the body. Earlier studies have shown indications that chronic inflammation of the prostate might create conditions that are favourable for the tumour cells. The bacterium Cutibacterium acnes is prevalent in prostate tissue from patients suffering from prostate cancer, which might indicate a link between the microorganism and this form of cancer. Tumour associated macrophages produce immunosuppressive proteins, such as the ligand PD-L1, a protein that might provide immunoevasive qualities for the tumour cells. The aim of the study was to examine whether macrophages that have been infected with either type I or type II C. acnes would produce a greater amount of PD-L1 than untreated macrophages. For this purpose, an ELISA test was performed to determine the concentrations of PD-L1 in the culture media. I found that macrophages that had been infected with the bacterium produced greater amounts of PD-L1 than untreated macrophages. The result of this study shows some indication that C. acnes could play a role in the proliferation of tumour cells and thus the spread of cancer through immunosuppresive mechanisms, although further studies are needed to confirm this hypothesis.
Subjects/Keywords: Macrophages; PD-L1; prostate cancer; Cutibacterium acnes; C. acnes; Makrofager; PD-L1; prostatacancer; Cutibacterium acnes; C. acnes; Immunology; Immunologi
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APA (6th Edition):
Härdin, J. (2020). Cutibacterium acnes inverkan på makrofagers produktion av PD-L1. (Thesis). Karlstad University. Retrieved from http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-78770
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Härdin, Jonas. “Cutibacterium acnes inverkan på makrofagers produktion av PD-L1.” 2020. Thesis, Karlstad University. Accessed January 19, 2021.
http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-78770.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Härdin, Jonas. “Cutibacterium acnes inverkan på makrofagers produktion av PD-L1.” 2020. Web. 19 Jan 2021.
Vancouver:
Härdin J. Cutibacterium acnes inverkan på makrofagers produktion av PD-L1. [Internet] [Thesis]. Karlstad University; 2020. [cited 2021 Jan 19].
Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-78770.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Härdin J. Cutibacterium acnes inverkan på makrofagers produktion av PD-L1. [Thesis]. Karlstad University; 2020. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-78770
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
14.
D'Almeida, Sénan.
Rôle de l’éctonucléotidase CD39 dans l’acquisition d’un phénotype immunorégulateur par les macrophages associés aux tumeurs : The ectonucleotidase CD39 in the acquisition of an immunosuppressive phenotype by tumor-associated macrophages.
Degree: Docteur es, Aspects moléculaires et cellulaires de la biologie, 2015, Angers
URL: http://www.theses.fr/2015ANGE0006
► Les macrophages associés aux tumeurs (TAM) sont des cellules immunorégulatrices qui s’accumulent massivement dans le microenvironnement (ME) tumoral. Chez les patients atteints de cancer de…
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▼ Les macrophages associés aux tumeurs (TAM) sont des cellules immunorégulatrices qui s’accumulent massivement dans le microenvironnement (ME) tumoral. Chez les patients atteints de cancer de l’ovaire (CO) ou de mésothéliome pleural malin (MPM), leur densité est associé à un mauvais pronostic. Le projet est porté sur la caractérisation des mécanismes impliqués dans leur recrutement et leur polarisation. L’éctonucléotidase CD39 hydrolyse l’ATP enadénosine extracellulaire, présentant des propriétés immunosuppressives. Nous avons montré que les TAMCD14+CD163+ isolés de CO et les M générés in vitro en présence de M-CSF, expriment un niveau élevé de CD39membranaire comparativement aux M immunostimulants. L’inhibition de CD39 diminue les fonctions immunorégulatrices des M CD163+CD39+high (i.e. IL-10 etPD-L1). Nous avons identifié la cytokine IL-27, sécrétée parles neutrophiles infiltrants la tumeur, comme rhéostat de l’expression de CD39. En conséquence, neutraliser l’IL-27pendant la différenciation des M en présence de M-CSF diminue l’expression de CD39 et PD-L1 ainsi que la sécrétiond’IL-10 par ces M . Parallèlement, nous avons montré que les effusions pleurales du MPM induisent la migration des monocytes via CCL2, polarisent les monocytes en MCD163+ et protègent des cellules tumorales de l’effet des agents cytotoxiques. L’ensemble de ces résultats suggère que le ciblage du recrutement (CCL2) et des molécules impliquées dans la polarisation des TAM (ligands du MCSFR,IL-27, CD39) représentent de nouvelles pistes thérapeutiques dans le traitement de certaines tumeurs solides.
Tumor-associated macrophages (TAM) are immunosuppressive cells that can massively accumulate in the tumor microenvironment (ME). In patients with ovarian cancer (OC) and malignant pleural mesothelioma (MPM), their density is correlated with poor prognosis. Targeting mediators that control the recruitment or the polarization of immunoregulatory macrophages (M ) represents therapeutic challenge to overcome tumor-associated immunosuppression. The ectonucleotidase CD39 hydrolyzes ATP into extracellular adenosine that exhibits potent immunosuppressive properties. We report here thatCD14+CD163+ TAM isolated from OC patients and Mgenerated in vitro with M-CSF, express high levels of the membrane ectonucleotidase CD39 compared to classically activated M . CD39 blockade diminished some of the immunosuppressive functions ofCD163+CD39hugh, such as IL-10 secretion. We identified the cytokine IL-27, secreted by tumorin-filtrating neutrophils, located close to infiltratingCD163+ M , as a major rheostat of CD39 expression and consequently, on the acquisition of immunoregulatory properties by macrophages. Accordingly, the depletion of IL-27 down-regulatedCD39, PD-L1 expression as well as IL-10 secretion byM-CSF-M . In parallel, we showed that pleural effusion of MPM induced monocytes migration via CCL2, the polarization of monocytes into CD163+ and induced protection to tumor cell death after chemotherapeutic treatments. Collectively, these data suggest that…
Advisors/Committee Members: Delneste, Yves (thesis director).
Subjects/Keywords: NTPDase1 CD39; Immunorégulation; Points de contrôles immunologiques (PD-L1); NTPDase1 CD39; Immunoregulation; Immune checkpoint (PD-L1); 610
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APA ·
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APA (6th Edition):
D'Almeida, S. (2015). Rôle de l’éctonucléotidase CD39 dans l’acquisition d’un phénotype immunorégulateur par les macrophages associés aux tumeurs : The ectonucleotidase CD39 in the acquisition of an immunosuppressive phenotype by tumor-associated macrophages. (Doctoral Dissertation). Angers. Retrieved from http://www.theses.fr/2015ANGE0006
Chicago Manual of Style (16th Edition):
D'Almeida, Sénan. “Rôle de l’éctonucléotidase CD39 dans l’acquisition d’un phénotype immunorégulateur par les macrophages associés aux tumeurs : The ectonucleotidase CD39 in the acquisition of an immunosuppressive phenotype by tumor-associated macrophages.” 2015. Doctoral Dissertation, Angers. Accessed January 19, 2021.
http://www.theses.fr/2015ANGE0006.
MLA Handbook (7th Edition):
D'Almeida, Sénan. “Rôle de l’éctonucléotidase CD39 dans l’acquisition d’un phénotype immunorégulateur par les macrophages associés aux tumeurs : The ectonucleotidase CD39 in the acquisition of an immunosuppressive phenotype by tumor-associated macrophages.” 2015. Web. 19 Jan 2021.
Vancouver:
D'Almeida S. Rôle de l’éctonucléotidase CD39 dans l’acquisition d’un phénotype immunorégulateur par les macrophages associés aux tumeurs : The ectonucleotidase CD39 in the acquisition of an immunosuppressive phenotype by tumor-associated macrophages. [Internet] [Doctoral dissertation]. Angers; 2015. [cited 2021 Jan 19].
Available from: http://www.theses.fr/2015ANGE0006.
Council of Science Editors:
D'Almeida S. Rôle de l’éctonucléotidase CD39 dans l’acquisition d’un phénotype immunorégulateur par les macrophages associés aux tumeurs : The ectonucleotidase CD39 in the acquisition of an immunosuppressive phenotype by tumor-associated macrophages. [Doctoral Dissertation]. Angers; 2015. Available from: http://www.theses.fr/2015ANGE0006
15.
Lereclus, Emilie.
Origine et rôles des cellules myéloïdes suppressives dans le sepsis : Origin and roles of myeloid-derived suppressor cells during sepsis.
Degree: Docteur es, Immunologie, oncologie et infectiologie, 2018, Limoges
URL: http://www.theses.fr/2018LIMO0060
► Les Myeloid-Derived Suppressor Cells (MDSC) sont une population hétérogène de cellules myéloïdes immatures, regroupées en deux sous-populations : les monocytiques-MDSC (M-MDSC) et les polymorphonucléaires-MDSC (PMN-MDSC).…
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▼ Les Myeloid-Derived Suppressor Cells (MDSC) sont une population hétérogène de cellules myéloïdes immatures, regroupées en deux sous-populations : les monocytiques-MDSC (M-MDSC) et les polymorphonucléaires-MDSC (PMN-MDSC). Ces cellules ont des capacités immunosuppressives et peuvent exprimer le ligand PD-L1 induisant l’anergie des lymphocytes T qui expriment le marqueur PD-1. Au cours du sepsis, divers bouleversements immunologiques surviennent, et la fonction majeure des MDSC est probablement de réguler l’hyper-inflammation en participant à l’état d’immunodépression rencontré chez les patients. Ceux-ci ont alors un risque de développer des infections secondaires, et de réactiver des virus jusque-là en latence. Notre étude a pour objectifs de mettre en évidence l’origine des MDSC dans le sepsis, et d’approfondir leurs rôles dans l’état d’immunosuppression, notamment dans la réactivation du Torque Teno Virus (TTV). Nos résultats montrent tant ex vivo qu’in vitro, que dans le sepsis, les MDSC sont produites par la moelle osseuse, sous l’influence du G-CSF et de l’IL-6. Ces cellules exprimant PD-L1, sont augmentées dans le sang très tôt dans le sepsis et persistes au cours de l’hospitalisation. L’augmentation de la charge virale du TTV est observée dans le sang périphérique des patients, mais n’est pas corrélée à la fréquence des MDSC. Ces résultats suggèrent que lors d’un sepsis, l’orage cytokinique stimule la production de MDSC exprimant PD-L1 par la moelle osseuse, qui une fois en périphérie, vont participer à l’immunosuppression générale.
Myeloid-Derived Suppressor Cells (MDSC) are a heterogeneous population of immature myeloid cell, and are regrouped in two subsets: the monocytic-MDSC (M-MDSC) and the polymorphonuclear-MDSC (PMN-MDSC). These cells have immunosuppressive capacities and mainly act on T cells. MDSC can express the ligand PD-L1 and induce PD-1 expressing-T cells exhaustion. During sepsis, several immunological changes occur, and MDSC probably downregulate the hyper-inflammatory state, contributing to the immunosuppression phase encountered in patients after a sepsis. Immunocompromised patients can develop secondary infections, and reactivate latent virus. The aims of our study were to highlight the origin of MDSC in sepsis, and to explore their roles in the immunosuppression state, especially in the Torque Teno Virus (TTV) reactivation. Our results show, both ex vivo and in vitro, that in sepsis, MDSC originate from bone marrow are induced by G-CSF and IL-6. These PD-L1 expressing-cells are increased in peripheral blood very early in sepsis, and persist during hospitalization. These MDSC are able to inhibit T cells in vitro. The increase of TTV viral load is observed in peripheral blood of patients but is not correlated with MDSC frequencies. These results suggest that during sepsis, the cytokine storm boosts PD-L1 expressing MDSC’s production by bone marrow, which contribute in peripheral blood to the immunosuppression
Advisors/Committee Members: Feuillard, Jean (thesis director), Alain, Sophie (thesis director).
Subjects/Keywords: MDSC; Sepsis; Moelle osseuse; PD-L1; Cytokines; TTV; MDSC; Sepsis; Bone marrow; PD-L1; Cytokines; TTV; 615.37
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APA ·
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APA (6th Edition):
Lereclus, E. (2018). Origine et rôles des cellules myéloïdes suppressives dans le sepsis : Origin and roles of myeloid-derived suppressor cells during sepsis. (Doctoral Dissertation). Limoges. Retrieved from http://www.theses.fr/2018LIMO0060
Chicago Manual of Style (16th Edition):
Lereclus, Emilie. “Origine et rôles des cellules myéloïdes suppressives dans le sepsis : Origin and roles of myeloid-derived suppressor cells during sepsis.” 2018. Doctoral Dissertation, Limoges. Accessed January 19, 2021.
http://www.theses.fr/2018LIMO0060.
MLA Handbook (7th Edition):
Lereclus, Emilie. “Origine et rôles des cellules myéloïdes suppressives dans le sepsis : Origin and roles of myeloid-derived suppressor cells during sepsis.” 2018. Web. 19 Jan 2021.
Vancouver:
Lereclus E. Origine et rôles des cellules myéloïdes suppressives dans le sepsis : Origin and roles of myeloid-derived suppressor cells during sepsis. [Internet] [Doctoral dissertation]. Limoges; 2018. [cited 2021 Jan 19].
Available from: http://www.theses.fr/2018LIMO0060.
Council of Science Editors:
Lereclus E. Origine et rôles des cellules myéloïdes suppressives dans le sepsis : Origin and roles of myeloid-derived suppressor cells during sepsis. [Doctoral Dissertation]. Limoges; 2018. Available from: http://www.theses.fr/2018LIMO0060
16.
Simard, François.
Implication of immune system in chondrosarcoma progression and therapeutic response : Could immunotherapy play a role in chondrosarcoma treatment ? : L’implication du système immunitaire dans la progression et la réponse thérapeutique du chondrosarcome : Est-ce que l’immunothérapie peut jouer un rôle dans le traitement du chondrosarcome ?.
Degree: Docteur es, Biologie, 2016, Lyon
URL: http://www.theses.fr/2016LYSE1073
► Le chondrosarcome (CHS) est caractérisé par une grande chimio et radiorésistance ; il y a un besoin urgent de nouvelles stratégies thérapeutiques pour cette tumeur.…
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▼ Le chondrosarcome (CHS) est caractérisé par une grande chimio et radiorésistance ; il y a un besoin urgent de nouvelles stratégies thérapeutiques pour cette tumeur. Parmi celles-ci, certaines approches d'immunothérapie pourraient être d'un grand intérêt. Nous étudions actuellement l'implication du système immunitaire dans la progression du CHS et la réponse thérapeutique à la fois sur des échantillons humains et dans le modèle de chondrosarcome de rat (SRC).Dans le CHS humain et de rat, des infiltrats immunitaires composés de lymphocytes et macrophages ont été identifiés dans la zone péritumorale. L’infiltration immunitaire est en corrélation avec l’évolution de la tumeur (grade, envahissement et taille). L'expression de PD1 et PDL1 ont été détectée dans les infiltrats immunitaires et cellules tumorales du CHS chez l’homme et le rat. Le niveau d'expression PD-L1 en corrélation avec la survie des patients et le taux de rechute. Dans le model SRC, la déplétion sélective de lymphocytes T a entrainé une accélération de la progression tumorale, tandis que la déplétion de macrophages l’a ralenti. Les splénocytes isolés de rats porteurs de CHS ont montré une cytotoxicité spécifique dirigée contre les cellules de chondrosarcome (27%), qui a diminué de manière significative avec des rats appauvrie en CD3 (11%). La voie de signalisation PI3K/mTOR ne peut pas être associée à une immunothérapie car elle induit une action immunosuppressive in vivo.L'environnement immunitaire contribue à la progression du CHS à la fois chez l’homme et chez le rat, ce qui suggère que une approche immunomodulatrice avec des anticorps bloquant PDL1 pourrait être testée pour le CHS
Chondrosarcoma is highly resistant to chemotherapy and radiation and there is an urgent need in developing new therapeutic strategies for this malignancy; among these, some immunotherapy approaches could be of great interest. We are currently investigating the immune system implication in chondrosarcoma progression and therapeutic response both on human samples and in rat chondrosarcoma model (SRC). In human and rat chondrosarcoma, immune infiltrates composed of lymphocytes and macrophages were identified in the peritumoral area. Immune infiltrates composition was found correlated with tumors characteristics and evolution (grade, invasiveness and size). Expression of PD-1 and PD-L1 was detected in CHS immune infiltrates, both in human and rat (and on tumor cells). PD-L1 expression level correlated with patients survival and relapse rate. In SRC, T lymphocytes depletion resulted in an accelerated tumor progression, while CD163+ macrophages depletion slowed down tumor progression. Splenocytes isolated from CHS bearing SRC showed a specific cytotoxicity directed against chondrosarcoma cells (27%), which significantly decreased in CD3 depleted SRC (11%). The immune environment contributes to CHS progression in both human and animal models, this associated with expression of immune checkpoint PD1/PDL1 suggest that immunomodulatory approaches with PD-L1 blocking antibody could…
Advisors/Committee Members: Blay, Jean-Yves (thesis director), Dutour, Aurélie (thesis director).
Subjects/Keywords: Chondrosarcome; Lymphocyte; PD-1; PD-L1; Macrophage; Immunothérapie; PI3K/Akt/mTOR; Immunosurveillance; Chondrosarcoma; Lymphocyte; PD-1; PD-L1; Macrophages; Immunotherapy; PI3K/Akt/mTOR; Immunosurveillance; 571.96
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APA (6th Edition):
Simard, F. (2016). Implication of immune system in chondrosarcoma progression and therapeutic response : Could immunotherapy play a role in chondrosarcoma treatment ? : L’implication du système immunitaire dans la progression et la réponse thérapeutique du chondrosarcome : Est-ce que l’immunothérapie peut jouer un rôle dans le traitement du chondrosarcome ?. (Doctoral Dissertation). Lyon. Retrieved from http://www.theses.fr/2016LYSE1073
Chicago Manual of Style (16th Edition):
Simard, François. “Implication of immune system in chondrosarcoma progression and therapeutic response : Could immunotherapy play a role in chondrosarcoma treatment ? : L’implication du système immunitaire dans la progression et la réponse thérapeutique du chondrosarcome : Est-ce que l’immunothérapie peut jouer un rôle dans le traitement du chondrosarcome ?.” 2016. Doctoral Dissertation, Lyon. Accessed January 19, 2021.
http://www.theses.fr/2016LYSE1073.
MLA Handbook (7th Edition):
Simard, François. “Implication of immune system in chondrosarcoma progression and therapeutic response : Could immunotherapy play a role in chondrosarcoma treatment ? : L’implication du système immunitaire dans la progression et la réponse thérapeutique du chondrosarcome : Est-ce que l’immunothérapie peut jouer un rôle dans le traitement du chondrosarcome ?.” 2016. Web. 19 Jan 2021.
Vancouver:
Simard F. Implication of immune system in chondrosarcoma progression and therapeutic response : Could immunotherapy play a role in chondrosarcoma treatment ? : L’implication du système immunitaire dans la progression et la réponse thérapeutique du chondrosarcome : Est-ce que l’immunothérapie peut jouer un rôle dans le traitement du chondrosarcome ?. [Internet] [Doctoral dissertation]. Lyon; 2016. [cited 2021 Jan 19].
Available from: http://www.theses.fr/2016LYSE1073.
Council of Science Editors:
Simard F. Implication of immune system in chondrosarcoma progression and therapeutic response : Could immunotherapy play a role in chondrosarcoma treatment ? : L’implication du système immunitaire dans la progression et la réponse thérapeutique du chondrosarcome : Est-ce que l’immunothérapie peut jouer un rôle dans le traitement du chondrosarcome ?. [Doctoral Dissertation]. Lyon; 2016. Available from: http://www.theses.fr/2016LYSE1073
17.
Khou, Sokchea.
Contribution des neutrophiles infiltrant les tumeurs dans la progression des carcinomes épidermoïdes cutanés : neutrophiles et cancer : Contribution of tumor-associated neutrophils in the course of cutaneous squamous cell carcinoma : neutrophils and cancer.
Degree: Docteur es, Interactions moléculaires et cellulaires, 2019, Université Côte d'Azur (ComUE)
URL: http://www.theses.fr/2019AZUR4014
► Les carcinomes cutanés constituent les cancers les plus fréquents chez l’homme et leur incidence est en constante croissance. Il en existe deux principaux types :…
(more)
▼ Les carcinomes cutanés constituent les cancers les plus fréquents chez l’homme et leur incidence est en constante croissance. Il en existe deux principaux types : les carcinomes baso-cellulaires et les carcinomes épidermoïdes. Les facteurs de risque sont principalement l’exposition aux rayons UV et l’immunosuppression. Ils sont traités par chirurgie ou par radiothérapie mais peuvent parfois évoluer vers des formes incurables. De nouvelles alternatives thérapeutiques sont donc nécessaires. L’immunothérapie est une récente révolution dans le traitement des cancers qui vise à réactiver l’immunité des patients cancéreux. Les carcinomes cutanés pourraient en bénéficier car ils se développent lors de situations d’immunosuppression. L’immunosurveillance implique à la fois les cellules immunitaires et le microenvironnement tumoral comme le stroma. Lorsque les réponses anti-tumorales, notamment médiées par les lymphocytes T CD8+ sont efficaces, on parle de phase d’élimination. Puis vient une phase d’équilibre où la tumeur reste stable et enfin, lors de la phase finale d’échappement, des mécanismes d’immunosuppression permettent à la tumeur de croître. Les neutrophiles, des cellules immunitaires de type myéloïde, sont recrutées très rapidement aux sites d’inflammation et au sein des cancers. Une méta-analyse récente sur 39 types de cancers humains a pu associer ces cellules aux plus mauvais pronostiques cliniques. Elles sont impliquées dans des fonctions anti-tumorales et pro-tumorales. Cette polarisation semble induite respectivement par l’interféron de type I et le TGF-β. Leur rôle lors de cancers et en particulier dans les carcinomes cutanés reste encore largement incompris. Notre objectif a été de caractériser les fonctions des neutrophiles et leur contribution au développement des carcinomes épidermoïdes. Pour cela, nous avons utilisé premièrement, un modèle de carcinogénèse cutanée chimio-induite. La tumorigénèse est séquentielle et donc très représentative du carcinome cutané chez l’homme. Dans ce modèle, nous observons une infiltration massive des neutrophiles au stade précancéreux et cancéreux. Une analyse de l’expression génique des neutrophiles isolés des lésions précancéreuses et cancéreuses et des peaux environnant ces lésions a été réalisée, qui montre une signature génique spécifique des neutrophiles des lésions, comparée aux peaux environnantes. Des comparaisons d’expression génique différentielle illustrent que les neutrophiles des lésions possèdent des fonctions pro-tumorales comparés aux neutrophiles des peaux.Deuxièmement, nous avons mis en place un modèle de greffe intradermique d’une lignée de carcinome épidermoïde. Une déplétion spécifique des neutrophiles retarde significativement la croissance tumorale, ce qui confirme le caractère pro-tumoral des neutrophiles. Nous avons caractérisé les mécanismes mis en jeu, qui incluent la génération de ROS et iNOS favorisant la croissance tumorale et une suppression de l’activation et de la prolifération des lymphocytes T CD8+ anti-tumoraux. Les neutrophiles…
Advisors/Committee Members: Braud, Véronique (thesis director).
Subjects/Keywords: Carcinomes cutanés; Neutrophiles; Protumoral; Immunosuppression; PD-L1; PD-1; Transcriptome; Cutaneous squamous cell carcinomas; Neutrophils; Protumoral; Immunosuppression; PD-L1; PD-1; Transcriptomic analysis
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APA ·
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APA (6th Edition):
Khou, S. (2019). Contribution des neutrophiles infiltrant les tumeurs dans la progression des carcinomes épidermoïdes cutanés : neutrophiles et cancer : Contribution of tumor-associated neutrophils in the course of cutaneous squamous cell carcinoma : neutrophils and cancer. (Doctoral Dissertation). Université Côte d'Azur (ComUE). Retrieved from http://www.theses.fr/2019AZUR4014
Chicago Manual of Style (16th Edition):
Khou, Sokchea. “Contribution des neutrophiles infiltrant les tumeurs dans la progression des carcinomes épidermoïdes cutanés : neutrophiles et cancer : Contribution of tumor-associated neutrophils in the course of cutaneous squamous cell carcinoma : neutrophils and cancer.” 2019. Doctoral Dissertation, Université Côte d'Azur (ComUE). Accessed January 19, 2021.
http://www.theses.fr/2019AZUR4014.
MLA Handbook (7th Edition):
Khou, Sokchea. “Contribution des neutrophiles infiltrant les tumeurs dans la progression des carcinomes épidermoïdes cutanés : neutrophiles et cancer : Contribution of tumor-associated neutrophils in the course of cutaneous squamous cell carcinoma : neutrophils and cancer.” 2019. Web. 19 Jan 2021.
Vancouver:
Khou S. Contribution des neutrophiles infiltrant les tumeurs dans la progression des carcinomes épidermoïdes cutanés : neutrophiles et cancer : Contribution of tumor-associated neutrophils in the course of cutaneous squamous cell carcinoma : neutrophils and cancer. [Internet] [Doctoral dissertation]. Université Côte d'Azur (ComUE); 2019. [cited 2021 Jan 19].
Available from: http://www.theses.fr/2019AZUR4014.
Council of Science Editors:
Khou S. Contribution des neutrophiles infiltrant les tumeurs dans la progression des carcinomes épidermoïdes cutanés : neutrophiles et cancer : Contribution of tumor-associated neutrophils in the course of cutaneous squamous cell carcinoma : neutrophils and cancer. [Doctoral Dissertation]. Université Côte d'Azur (ComUE); 2019. Available from: http://www.theses.fr/2019AZUR4014
18.
Kostine, Marie.
Defining the immune microenvironment in sarcoma : could immunotherapy be part of the treatment strategy in sarcoma patients ? : Etude du microenvironnement immunitaire dans les sarcomes : pourrait-il y avoir une place pour l'immunothérapie dans la stratégie thérapeutique ?.
Degree: Docteur es, Biologie Cellulaire et Physiopathologie, 2018, Bordeaux
URL: http://www.theses.fr/2018BORD0387
► La chirurgie est la pierre angulaire du traitement curatif des sarcomes, lorsqu’elle est possible. En revanche, en cas de maladie avancée ou métastatique, les traitements…
(more)
▼ La chirurgie est la pierre angulaire du traitement curatif des sarcomes, lorsqu’elle est possible. En revanche, en cas de maladie avancée ou métastatique, les traitements systémiques ont une efficacité assez limitée avec un réel besoin de nouvelles options thérapeutiques. Le récent succès de l’immunothérapie dans les tumeurs épithéliales soulève donc la question de la possibilité d’une telle approche dans les sarcomes, et surtout pour quels sous-types histologiques. L’objectif de ce travail de thèse était d’obtenir des données précliniques en caractérisant le microenvironnement immunitaire au sein de trois types de sarcomes potentiellement candidats à l’immunothérapie, prérequis indispensable avant d’envisager une application clinique : 1) Dans le chondrosarcome, l’expression de PD-L1 a été retrouvée exclusivement dans près de 50% des chondrosarcomes dédifférenciés, et s’associait à une infiltration lymphocytaire T et l’expression des molécules HLA de classe I. Ces données incitent donc à inclure les patients avec ce sous type de chondrosarcome dans des essais cliniques évaluant un traitement anti PD-1/PD-L1. 2) Dans l’ostéosarcome, un infiltrat lymphocytaire T était observé de façon bien plus importante dans les lésions métastatiques que dans lésions primitives ou rechutes locales. De plus, l’expression de PD-L1 était retrouvée dans presque 50% des métastases mais pas ou peu dans la tumeur primitive correspondante, traduisant ici une dynamique d’échappement au système immunitaire lors de la progression de la maladie. Une stratégie ciblée sur les lymphocytes T visant à amplifier et potentialiser cette réponse immune préexistante dans les lésions métastatiques pourrait donc offrir un bénéfice clinique. 3) Dans le léiomyosarcome, les molécules HLA de classe I étaient fortement exprimées et l’expression de PD-L1 retrouvée dans 30% des tumeurs de haut grade, également très infiltrées par des macrophages immunosuppresseurs CD163+. Une importante infiltration de macrophages CD163+ était un marqueur indépendant de mauvais pronostic pour la survie, indiquant l’intérêt de d’une approche ciblée visant les macrophages dans ce type de sarcome, éventuellement en association avec un traitement anti PD-1/PD-L1.
Local control with adequate surgery is the cornerstone of sarcoma treatment. However, most sarcoma lack effective systemic therapies in case of advanced disease, emphasizing an unmet medical need for new therapeutic targets. The recent success of immunotherapy in epithelial malignancies raises the question whether such therapies, and which ones, would be applicable in sarcomas. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in three sarcoma subtypes potentially candidate to immunotherapy: 1) In chondrosarcoma, PD-L1 expression was exclusively found in nearly 50% of the dedifferentiated subtype, in association with immune-infiltrating cells and HLA class I expression. These data provide rationale for including such patients in clinical trials with PD-1/PD-L1-targeted therapies.…
Advisors/Committee Members: Italiano, Antoine (thesis director).
Subjects/Keywords: Sarcome; Immunothérapie; Pd-1/pd-L1; Hla; Macrophages associés aux tumeurs; Lymphocytes T; Sarcoma; Immunotherapy; Pd-1/pd-L1; Hla; Tumor-Associated macrophages; T cells
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APA (6th Edition):
Kostine, M. (2018). Defining the immune microenvironment in sarcoma : could immunotherapy be part of the treatment strategy in sarcoma patients ? : Etude du microenvironnement immunitaire dans les sarcomes : pourrait-il y avoir une place pour l'immunothérapie dans la stratégie thérapeutique ?. (Doctoral Dissertation). Bordeaux. Retrieved from http://www.theses.fr/2018BORD0387
Chicago Manual of Style (16th Edition):
Kostine, Marie. “Defining the immune microenvironment in sarcoma : could immunotherapy be part of the treatment strategy in sarcoma patients ? : Etude du microenvironnement immunitaire dans les sarcomes : pourrait-il y avoir une place pour l'immunothérapie dans la stratégie thérapeutique ?.” 2018. Doctoral Dissertation, Bordeaux. Accessed January 19, 2021.
http://www.theses.fr/2018BORD0387.
MLA Handbook (7th Edition):
Kostine, Marie. “Defining the immune microenvironment in sarcoma : could immunotherapy be part of the treatment strategy in sarcoma patients ? : Etude du microenvironnement immunitaire dans les sarcomes : pourrait-il y avoir une place pour l'immunothérapie dans la stratégie thérapeutique ?.” 2018. Web. 19 Jan 2021.
Vancouver:
Kostine M. Defining the immune microenvironment in sarcoma : could immunotherapy be part of the treatment strategy in sarcoma patients ? : Etude du microenvironnement immunitaire dans les sarcomes : pourrait-il y avoir une place pour l'immunothérapie dans la stratégie thérapeutique ?. [Internet] [Doctoral dissertation]. Bordeaux; 2018. [cited 2021 Jan 19].
Available from: http://www.theses.fr/2018BORD0387.
Council of Science Editors:
Kostine M. Defining the immune microenvironment in sarcoma : could immunotherapy be part of the treatment strategy in sarcoma patients ? : Etude du microenvironnement immunitaire dans les sarcomes : pourrait-il y avoir une place pour l'immunothérapie dans la stratégie thérapeutique ?. [Doctoral Dissertation]. Bordeaux; 2018. Available from: http://www.theses.fr/2018BORD0387
19.
Inoue, Yusuke.
Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer : 非小細胞肺がんにおけるPD-L1、PD-L2遺伝子コピー数増加の臨床的意義.
Degree: 博士（医学）, 2017, Hamamatsu University School of Medicine / 浜松医科大学
URL: http://hdl.handle.net/10271/3219
► New reliable biomarkers are needed to predict the response to immune checkpoint inhibitors against programmed death‑1 (PD‑1) and its ligand (PD‑L1), because PD‑L1 expression on…
(more)
▼ New reliable biomarkers are needed to predict the response to immune checkpoint inhibitors against programmed death‑1 (PD‑1) and its ligand (PD‑L1), because PD‑L1 expression on tumor cells has limited power for selecting patients who may benefit from such therapy. Here we investigated the significance of PD‑L1 and PD‑L2 gene copy number gains using fluorescence in situ hybridization as well as PD‑L1 and PD‑L2 expression in 654 patients with resected non‑small‑cell lung cancer. The prevalence of PD‑L1 amplification and polysomy was 3.1% and 13.2%, respectively. The PD‑L1 gene copy number status was in agreement with both the PD‑L2 and Janus kinase 2 gene copy number statuses. PD‑L1 and PD‑L2 expression was observed in 30.7% and 13.1%, respectively. Both PD‑L1 copy number gains and expression were associated with smoking‑related tumors. Tumor cells with PD‑L1 genomic gains exhibited significantly higher levels of PD‑L1 expression than those without, but PD‑L2 copy number gains were not related to PD‑L2 augmentation. PD‑L1 gene amplification and polysomy were independently associated with PD‑L1 expression, with high immune infiltrates and EGFR expression in a multivariate logistic regression model. Comparative analysis between primary tumors and synchronous regional lymph node metastases revealed that the PD‑L1 gene copy number alterations were highly consistent and reproducible compared with the PD‑L1 expression. Both PD‑L1 amplification and level of protein expression were predictors of poor survival using Cox univariate analyses. Therefore, we conclude that an increase in PD‑L1 gene copy number can be a feasible alternative biomarker for predicting response to anti‑PD‑1/PD‑L1 therapy.
浜松医科大学学位論文 医博第744号（平成29年3月13日）
Subjects/Keywords: PD‑L1; PD‑L2; amplification; copy number; non‑small‑cell lung cancer
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APA (6th Edition):
Inoue, Y. (2017). Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer : 非小細胞肺がんにおけるPD-L1、PD-L2遺伝子コピー数増加の臨床的意義. (Thesis). Hamamatsu University School of Medicine / 浜松医科大学. Retrieved from http://hdl.handle.net/10271/3219
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Inoue, Yusuke. “Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer : 非小細胞肺がんにおけるPD-L1、PD-L2遺伝子コピー数増加の臨床的意義.” 2017. Thesis, Hamamatsu University School of Medicine / 浜松医科大学. Accessed January 19, 2021.
http://hdl.handle.net/10271/3219.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Inoue, Yusuke. “Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer : 非小細胞肺がんにおけるPD-L1、PD-L2遺伝子コピー数増加の臨床的意義.” 2017. Web. 19 Jan 2021.
Vancouver:
Inoue Y. Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer : 非小細胞肺がんにおけるPD-L1、PD-L2遺伝子コピー数増加の臨床的意義. [Internet] [Thesis]. Hamamatsu University School of Medicine / 浜松医科大学; 2017. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/10271/3219.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Inoue Y. Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer : 非小細胞肺がんにおけるPD-L1、PD-L2遺伝子コピー数増加の臨床的意義. [Thesis]. Hamamatsu University School of Medicine / 浜松医科大学; 2017. Available from: http://hdl.handle.net/10271/3219
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
East Carolina University
20.
Atwell, Druid Carlisle.
Identification of Biomarkers in Non-Small Cell Lung Cancer Patients Treated with PD-1 Monoclonal Antibody Immunotherapy.
Degree: MS, MS-Biomedical Science, 2018, East Carolina University
URL: http://hdl.handle.net/10342/7016
► Cancer immunotherapy works by taking a patient's existing immune system and priming it to recognize cancer cells in order for immune cells to mount an…
(more)
▼ Cancer immunotherapy works by taking a patient's existing immune system and priming it to recognize cancer cells in order for immune cells to mount an effective response to the disease. This is a less invasive means of treating cancer for the patient. However current immunotherapy does come with its own unique side effects such as auto immune disorders that manifest in the patients' treatment due to the blocking of essential immune regulatory checkpoints. In this study, patients are treated with drugs nivolumab and pembrolizumab, both of which are
PD-1 (Programmed Death Receptor 1) monoclonal antibodies. These antibodies bind to
PD-1 and prevent ligand interaction with
PD-
L1.
PD-1 is a receptor expressed on the surface of activated B-cells, macrophages and T-cells. When
PD-1 is activated by
PD-
L1 a signal propagates from the receptor to inside the cell that results in the apoptosis of the cell that expresses
PD-1. The activation of
PD-1 on activated T-cells ultimately results in a reduction of T-cell proliferation and IFN-[gamma] secretion. An apoptotic signal occurs through the inhibition of the cell survival signal that is propagated through the PI3K pathway. While there is knowledge on how the expression and activation of
PD-1 on immune cells regulates the progression of cancer, there is a lack of evidence to suggest biomarkers in non-small cell lung cancer patients for optimizing immunotherapy. This study serves to identify biomarkers in non-small cell lung cancer patients undergoing
PD-1 monoclonal antibody immunotherapy. To accomplish this, blood samples were collected from non-small cell lung cancer patients undergoing the immunotherapy treatment and the cell counts were taken. Cell types of interest include cytotoxic T-cells, helper T-cells, B-cells, and granulocytes. Cytotoxic T-cells were identified by CD8 expression, a known marker of cytotoxic T-cells. Helper T-cells were identified by CD4 expression and B-cells were identified by CD19 expression, both of which are known markers of helper T-cells and B-cells, respectively. Secondly, this study investigated the expression levels of known immune regulatory genes and how these changed over the course of the immunotherapy treatment. Known immune regulatory genes included
PD-
L1,
PD-1, CTLA4, CD28, A2A, CD80 and CD86. The expression levels of the proton sensing family of G-protein coupled receptors (G2A, GPR4, OGR1 and TDAG8) were also investigated. Thirdly, we investigated how tumor cell expression of
PD-1 and
PD-
L1 was altered when introduced into an acidic environment. Due to the tumor microenvironment being characteristically acidic this would provide insight on how anti
PD-1 and anti
PD-
L1 immunotherapies could potentially be used in various cancers and may also lead to the development of potential future combination therapies. Our study shows that approximately 90% of patients exhibited an increase in cytotoxic T-cell counts with 50% of patients achieving healthy donor cytotoxic T-cell counts after receiving immunotherapy. Additionally 2 patients out of…
Advisors/Committee Members: Yang, Li V (advisor).
Subjects/Keywords: PD-1; PD-L1; Antibodies, Monoclonal; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Immunotherapy; Humans
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APA ·
Chicago ·
MLA ·
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CSE |
Export
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Manager
APA (6th Edition):
Atwell, D. C. (2018). Identification of Biomarkers in Non-Small Cell Lung Cancer Patients Treated with PD-1 Monoclonal Antibody Immunotherapy. (Masters Thesis). East Carolina University. Retrieved from http://hdl.handle.net/10342/7016
Chicago Manual of Style (16th Edition):
Atwell, Druid Carlisle. “Identification of Biomarkers in Non-Small Cell Lung Cancer Patients Treated with PD-1 Monoclonal Antibody Immunotherapy.” 2018. Masters Thesis, East Carolina University. Accessed January 19, 2021.
http://hdl.handle.net/10342/7016.
MLA Handbook (7th Edition):
Atwell, Druid Carlisle. “Identification of Biomarkers in Non-Small Cell Lung Cancer Patients Treated with PD-1 Monoclonal Antibody Immunotherapy.” 2018. Web. 19 Jan 2021.
Vancouver:
Atwell DC. Identification of Biomarkers in Non-Small Cell Lung Cancer Patients Treated with PD-1 Monoclonal Antibody Immunotherapy. [Internet] [Masters thesis]. East Carolina University; 2018. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/10342/7016.
Council of Science Editors:
Atwell DC. Identification of Biomarkers in Non-Small Cell Lung Cancer Patients Treated with PD-1 Monoclonal Antibody Immunotherapy. [Masters Thesis]. East Carolina University; 2018. Available from: http://hdl.handle.net/10342/7016
University of Toronto
21.
Lee, Minji.
Investigating Molecular Differences related to T-bet-Positive Tumor-infiltrating Lymphocytes in Axillary Node-negative Breast Cancer.
Degree: 2017, University of Toronto
URL: http://hdl.handle.net/1807/77837
► The clinical outcomes of axillary node-negative (ANN) breast cancer (BC) patients were previously shown to be positively associated with T-bet+ tumor-infiltrating lymphocytes (TILs). This study…
(more)
▼ The clinical outcomes of axillary node-negative (ANN) breast cancer (BC) patients were previously shown to be positively associated with T-bet+ tumor-infiltrating lymphocytes (TILs). This study identified differences in miRNA and gene expression, and in PD-L1 expression between T-bet+/high and T-bet-/low tumors that provided insights into how T-bet+ TIL- mediated immunesurveillance may relate to tumor characteristics and disease outcome in ANN BC. The differentially expressed (DE) miRNAs were associated with intrinsic cancer-related pathways and immune-modulatory activities. miR-135a, in particular, was downregulated in T- bet+/high tumors, and was shown to be a direct suppressor of CXCL10, a T lymphocyte-recruiting chemokine. Among the DE genes, BRD4, a co-activator of NF-kB, was upregulated in T-bet+/high tumors at both mRNA and protein levels, suggesting a link between BRD4 expression and T-bet+-TIL-mediated inflammatory activities. The mRNA expression of PD-L1, a T-cell inhibitory marker, was associated with T-bet+ TILs, and basal subtype.
M.Sc.
Advisors/Committee Members: Andrulis, Irene L, Laboratory Medicine and Pathobiology.
Subjects/Keywords: BRD4; Breast Cancer; miRNA; PD-L1; T-bet; TIL; 0307
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APA ·
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Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Lee, M. (2017). Investigating Molecular Differences related to T-bet-Positive Tumor-infiltrating Lymphocytes in Axillary Node-negative Breast Cancer. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/77837
Chicago Manual of Style (16th Edition):
Lee, Minji. “Investigating Molecular Differences related to T-bet-Positive Tumor-infiltrating Lymphocytes in Axillary Node-negative Breast Cancer.” 2017. Masters Thesis, University of Toronto. Accessed January 19, 2021.
http://hdl.handle.net/1807/77837.
MLA Handbook (7th Edition):
Lee, Minji. “Investigating Molecular Differences related to T-bet-Positive Tumor-infiltrating Lymphocytes in Axillary Node-negative Breast Cancer.” 2017. Web. 19 Jan 2021.
Vancouver:
Lee M. Investigating Molecular Differences related to T-bet-Positive Tumor-infiltrating Lymphocytes in Axillary Node-negative Breast Cancer. [Internet] [Masters thesis]. University of Toronto; 2017. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1807/77837.
Council of Science Editors:
Lee M. Investigating Molecular Differences related to T-bet-Positive Tumor-infiltrating Lymphocytes in Axillary Node-negative Breast Cancer. [Masters Thesis]. University of Toronto; 2017. Available from: http://hdl.handle.net/1807/77837
University of Southern California
22.
Usher, Joshua.
Use of cell-free nucleic acids in associating PD-L1 gene
expression with presence of driver mutations in DNA and
demographics across different cancers.
Degree: MS, Biostatistics, 2016, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/640124/rec/7732
► Introduction: Measuring allele frequencies of somatic gene mutations in DNA and levels of relative gene expressions in RNA can now be measured using cell-free nucleic…
(more)
▼ Introduction: Measuring allele frequencies of somatic
gene mutations in DNA and levels of relative gene expressions in
RNA can now be measured using cell-free nucleic acids isolated from
liquid biopsies (plasma fractionated from blood samples). Liquid
biopsies may replace the traditional pioneer method for monitoring
genetic mutations and levels of gene expressions from the tissue
biopsies of cancer patients. ❧ Methods: Blood samples were
collected from cancer patients from 5 different tumor types
(colorectal, lung, prostate, gastric, and breast). Plasma was
fractionated from blood samples and nucleic acids were extracted.
RNA was reverse-transcribed into cDNA using random primers, and
then analyzed by quantitative RT-PCR using appropriate
gene-specific primers. The cDNA of
PD-
L1 was quantitated. Mutations
in subsequent genes (cfDNA) were measured for same patients and
then compared with that of their individual
PD-
L1 gene expression
detection frequencies. β-actin expression was used as the
denominator gene representing total RNA. ❧ Results: The presence of
relative
PD-
L1 gene expression in cfRNA was not statistically
associated with the somatic cfDNA mutation measured in the BRAF
gene (V600E) (p = 0.6286, Fisher’s Exact). The presence of relative
PD-
L1 gene expression in cfRNA was (preliminarily) statistically
associated with the somatic cfDNA mutations measured in the EGFR
gene (L858R and exon 19 deletions) (p = 0.1940, Fisher’s Exact).
The presence of relative
PD-
L1 gene expression in cfRNA was
(preliminarily) statistically associated with the somatic cfDNA
mutations measured in the KRAS gene (G12A, G12C, G12D, G12S, G12V,
G13D) (p = 0.0466, Fisher’s Exact). ❧ Conclusion: The frequency of
PD-
L1 expression among cancer patients harboring mutations within
specific genes, including BRAF, KRAS, and EGFR were concordant with
that found across numerous studies using nucleic acids isolated
from tumor tissue biopsies. Ultimately, more research is needed to
grasp a valid understanding of the technology behind the liquid
biopsy, as it’s still at its infancy.
Advisors/Committee Members: Goshen, Susan (Committee Chair).
Subjects/Keywords: PD-L1; BRAF; KRAS; EGFR; cell-free; DNA; RNA
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Usher, J. (2016). Use of cell-free nucleic acids in associating PD-L1 gene
expression with presence of driver mutations in DNA and
demographics across different cancers. (Masters Thesis). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/640124/rec/7732
Chicago Manual of Style (16th Edition):
Usher, Joshua. “Use of cell-free nucleic acids in associating PD-L1 gene
expression with presence of driver mutations in DNA and
demographics across different cancers.” 2016. Masters Thesis, University of Southern California. Accessed January 19, 2021.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/640124/rec/7732.
MLA Handbook (7th Edition):
Usher, Joshua. “Use of cell-free nucleic acids in associating PD-L1 gene
expression with presence of driver mutations in DNA and
demographics across different cancers.” 2016. Web. 19 Jan 2021.
Vancouver:
Usher J. Use of cell-free nucleic acids in associating PD-L1 gene
expression with presence of driver mutations in DNA and
demographics across different cancers. [Internet] [Masters thesis]. University of Southern California; 2016. [cited 2021 Jan 19].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/640124/rec/7732.
Council of Science Editors:
Usher J. Use of cell-free nucleic acids in associating PD-L1 gene
expression with presence of driver mutations in DNA and
demographics across different cancers. [Masters Thesis]. University of Southern California; 2016. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/640124/rec/7732
University of Sydney
23.
Williams, Marissa.
Aberrant MicroRNA Expression in Malignant Pleural Mesothelioma
.
Degree: 2018, University of Sydney
URL: http://hdl.handle.net/2123/19754
► Malignant Pleural Mesothelioma (MPM) is an aggressive asbestos related malignancy. The global downregulation of microRNA (miRNA) expression is common in MPM, however, the mechanisms driving…
(more)
▼ Malignant Pleural Mesothelioma (MPM) is an aggressive asbestos related malignancy. The global downregulation of microRNA (miRNA) expression is common in MPM, however, the mechanisms driving the downregulation of some tumour suppressor miRNAs, including the miR-15 family, are yet to be clarified. In this study, multiple mechanisms, including a combination of genomic deletion, DNA methylation and transcriptional repression, were demonstrated to lead to downregulation of miR-15a/16-1, miR-15b/16-2, miR-193a-3p, and miR-34c. The c-Myc oncogene was evidenced to transcriptionally repress expression of miR-15/16, predominately via association with the miR-15b/16-2 locus. The majority of MPM patients become refractory to the first-line treatment of pemetrexed and cisplatin chemotherapy due to chemo-resistance. MiRNAs belonging to the miR-15/16 and -34 families have been previously implicated in the development of drug resistance in other malignancies but their role in MPM chemo-resistance is largely unexplored. The expression of miR-15a/16-1 and miR-34a was downregulated in cell lines with acquired resistance to chemotherapy. Restoration of miRNA expression by mimic transfection led to the sensitisation of MPM cell lines to chemotherapy induced cytotoxicity and apoptosis, partly via repression of BCL2. Immune checkpoint inhibition of the PD-1/PD-L1 axis is an emerging therapeutic field in MPM. PD-L1 expression is upregulated and associated with poor prognosis in MPM, but the molecular mechanisms causing its dysregulation are poorly understood. In this study, reduced miRNA expression was related to elevated PD-L1 levels in the MPM patient panel. Restoration of miRNA expression led to downregulation of PD-L1 mRNA and protein expression via association with the 3’UTR region of the PD-L1 mRNA in MPM cell lines. Results from this study, and others, suggests that restoration of aberrant miRNA expression has the potential to improve, or lead to new targets for MPM therapy.
Subjects/Keywords: mesothelioma;
microRNA;
c-Myc;
drug resistance;
PD-L1
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APA ·
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MLA ·
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CSE |
Export
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Manager
APA (6th Edition):
Williams, M. (2018). Aberrant MicroRNA Expression in Malignant Pleural Mesothelioma
. (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/19754
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Williams, Marissa. “Aberrant MicroRNA Expression in Malignant Pleural Mesothelioma
.” 2018. Thesis, University of Sydney. Accessed January 19, 2021.
http://hdl.handle.net/2123/19754.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Williams, Marissa. “Aberrant MicroRNA Expression in Malignant Pleural Mesothelioma
.” 2018. Web. 19 Jan 2021.
Vancouver:
Williams M. Aberrant MicroRNA Expression in Malignant Pleural Mesothelioma
. [Internet] [Thesis]. University of Sydney; 2018. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/2123/19754.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Williams M. Aberrant MicroRNA Expression in Malignant Pleural Mesothelioma
. [Thesis]. University of Sydney; 2018. Available from: http://hdl.handle.net/2123/19754
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Otago
24.
Ahn, Jeong Hyun (Antonio).
Constitutive PD-L1 expression in melanoma
.
Degree: University of Otago
URL: http://hdl.handle.net/10523/10079
► Treatment of melanoma based on targeted therapy and immunotherapy has dramatically advanced over the past decade. Advances in targeted therapy have been based on inhibition…
(more)
▼ Treatment of melanoma based on targeted therapy and immunotherapy has dramatically advanced over the past decade. Advances in targeted therapy have been based on inhibition of the MAPK pathway while for immunotherapy, advances have been based on blocking immune checkpoint proteins such as the
PD-1/
PD-
L1 axis.
PD-
L1 serves as a potent immune suppressor of the immune response enabling cancer cells to escape the immune surveillance. Recently, it was reported in several studies that resistance to MAPK pathway inhibitors can be accompanied by increases in constitutive
PD-
L1 expression in melanoma, highlighting the importance of understanding the underlying regulation of
PD-
L1 expression.
However, the mechanism regulating constitutive
PD-
L1 expression remains unclear in melanoma. In this study, one of the aims was to investigate whether DNA methylation plays a role in
PD-
L1 expression. Firstly, it was found that melanoma cell lines with constitutive
PD-
L1 expression have a marked loss of global DNA methylation (hypomethylation), particularly in the intergenic regions and repeat elements, which suggested an altered epigenomic landscape. A number of endogenous retrovirus (ERV) elements that reside in the intergenic region were increased in expression in the constitutive
PD-
L1 cell lines. This was accompanied by activation of the innate immune response and transcription factors that can upregulate
PD-
L1 levels. Intergenic lncRNAs that are in close proximity to immune related genes were also upregulated in the constitutive
PD-
L1 cell lines. Moreover, DNMTi (global demethylation) mediated
PD-
L1 upregulation was revealed to increase many of the same innate immune response genes and transcription factors that were upregulated in the constitutive
PD-
L1 samples supporting the role of DNA hypomethylation in
PD-
L1 expression.
Furthermore, how
PD-
L1 expression is associated with resistance to MAPK targeted inhibitors remains unclear. Here, it was found that constitutive
PD-
L1 expression is associated with a transcriptomic state that is characteristic for dedifferentiation which is mediated by the loss of SOX10 expression and upregulation of other transcription factors such as SOX9. Moreover, constitutive
PD-
L1 samples were associated with a reduced expression of genes involved in oxidative phosphorylation demonstrating an altered metabolic program.
Overall, we found evidence that supports constitutive
PD-
L1 expression in melanoma is regulated by the viral mimicry pathway via global hypomethylation. Furthermore, constitutive
PD-
L1 expression is closely associated with dedifferentiation mediated by loss of SOX10 which provides insight as to why
PD-
L1 expression increases upon development of therapy resistance.
Advisors/Committee Members: Eccles, Michael (advisor).
Subjects/Keywords: Melanoma;
PD-L1;
Constitutive
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APA (6th Edition):
Ahn, J. H. (. (n.d.). Constitutive PD-L1 expression in melanoma
. (Doctoral Dissertation). University of Otago. Retrieved from http://hdl.handle.net/10523/10079
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Chicago Manual of Style (16th Edition):
Ahn, Jeong Hyun (Antonio). “Constitutive PD-L1 expression in melanoma
.” Doctoral Dissertation, University of Otago. Accessed January 19, 2021.
http://hdl.handle.net/10523/10079.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
MLA Handbook (7th Edition):
Ahn, Jeong Hyun (Antonio). “Constitutive PD-L1 expression in melanoma
.” Web. 19 Jan 2021.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Vancouver:
Ahn JH(. Constitutive PD-L1 expression in melanoma
. [Internet] [Doctoral dissertation]. University of Otago; [cited 2021 Jan 19].
Available from: http://hdl.handle.net/10523/10079.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Council of Science Editors:
Ahn JH(. Constitutive PD-L1 expression in melanoma
. [Doctoral Dissertation]. University of Otago; Available from: http://hdl.handle.net/10523/10079
Note: this citation may be lacking information needed for this citation format:
No year of publication.
25.
Auclair, Héloïse.
Etude des homologies phénotypiques et fonctionnelles des lymphocytes B en latence III de l'EBV avec les cellules B régulatrices, implication de l'axe PD-1/PD-L1 : Study of phenotypic and functional homologies of EBV latency III B-lymphocytes with regulatory B cells, involvement of the PD-1 / PD-L1 axis.
Degree: Docteur es, Immunologie, Cancérologie, Virologie, 2017, Limoges
URL: http://www.theses.fr/2017LIMO0032
► Le virus d’Epstein-Barr (EBV) est le premier virus transformant à avoir été identifié chez l’Homme. Il infecte plus de 90% de la population adulte mondiale,…
(more)
▼ Le virus d’Epstein-Barr (EBV) est le premier virus transformant à avoir été identifié chez l’Homme. Il infecte plus de 90% de la population adulte mondiale, persistant sous forme épisomale dans le compartiment B mémoire tout au long de la vie de l’hôte. Lors de la primo-infection et lors de phases de réactivation du virus, les cellules B immortalisées sont en programme de latence III, aussi appelée phase de prolifération, où l’ensemble des protéines de latence sont exprimées. Lorsque les hôtes sont immunocompétents, un équilibre entre hôte et virus s’établit et la plupart des cellules B infectées sont éliminées par le système immunitaire de l’hôte, principalement par les lymphocytes T cytotoxiques. En cas de déficit immunitaire, il peut y avoir émergence de lymphomes, tels que les désordres lymphoprolifératifs des patients immunodéprimés (PTLDs), les lymphomes non-Hodgkiniens (LNH) et Hodgkiniens (LH). Les travaux antérieurs du laboratoire ont permis de révéler que l’immuno-inhibiteur PD-L1/B7-H1/CD274 est surexprimé à la surface des lymphocytes B en latence III de l’EBV. L’interleukine-10 (IL-10) est également sécrétée par ces cellules. Ces caractéristiques sont communes aux cellules B régulatrices (Bregs). Le but de ma thèse était d’interroger les caractéristiques immuno-modulatrices des cellules B en latence III de l’EBV, dans le cadre des propriétés des Bregs. Nous montrons que les cellules B en latence III de l’EBV possèdent les déterminants antigéniques communs aux Bregs immatures (CD24High CD38High PD-L1High), associée à une surexpression des cytokines immunosuppressives cardinales des Bregs (IL-10, TGF-β1 et IL-35). Nous montrons que les cellules B en latence III de l’EBV peuvent conduire à la mort des cellules T CD4 autologues, ainsi qu’à l’inhibition de la prolifération des lymphocytes T CD4 et CD8, au profit de l’expansion de lymphocytes T régulateurs (Tregs). Nous avons trouvé que cette expansion est médiée par l’axe PD-1/PD-L1. Ces travaux mettent en évidence un nouveau mécanisme de l’EBV concernant le détournement du système immunitaire de l’hôte, augmentant ses capacités oncogéniques.
The Epstein-Barr virus (EBV) is the first transforming virus discovered in humans. It infects more than 90% of the global adult population, persisting in an episomal form in the memory B-cell compartment throughout the life of the host. During primo-infection and during phases of viral reactivation, immortalized B-cells are in latency III, also called the proliferation program, in which the full range of latency proteins are expressed. In immunocompetent subjects, a balance between virus and host is established, and most infected B-cells are eliminated by the host’s immune system, mainly by cytotoxic T lymphocytes. Deficit of the immune system may lead to lymphomagenesis, such as post-transplantation lymphoproliferative disorders (PTLDs), non-Hodgkin’s (NHL) or Hodgkin’s lymphomas (HL). Previous studies in the lab revealed that the immuno-inhibitor PD-L1/B7-H1/CD274 was overexpressed on the surface of EBV latency III…
Advisors/Committee Members: Feuillard, Jean (thesis director), Jayat-Vignoles, Chantal (thesis director).
Subjects/Keywords: EBV; Latence III; IL-10; Immunosuppression; Bregs; Tregs; Axe PD-1/PD-L1; EBV; Latency III; IL-10; Immunosuppression; Bregs; Tregs; PD-1/PD-L1axis; 615.37; 616.994
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Auclair, H. (2017). Etude des homologies phénotypiques et fonctionnelles des lymphocytes B en latence III de l'EBV avec les cellules B régulatrices, implication de l'axe PD-1/PD-L1 : Study of phenotypic and functional homologies of EBV latency III B-lymphocytes with regulatory B cells, involvement of the PD-1 / PD-L1 axis. (Doctoral Dissertation). Limoges. Retrieved from http://www.theses.fr/2017LIMO0032
Chicago Manual of Style (16th Edition):
Auclair, Héloïse. “Etude des homologies phénotypiques et fonctionnelles des lymphocytes B en latence III de l'EBV avec les cellules B régulatrices, implication de l'axe PD-1/PD-L1 : Study of phenotypic and functional homologies of EBV latency III B-lymphocytes with regulatory B cells, involvement of the PD-1 / PD-L1 axis.” 2017. Doctoral Dissertation, Limoges. Accessed January 19, 2021.
http://www.theses.fr/2017LIMO0032.
MLA Handbook (7th Edition):
Auclair, Héloïse. “Etude des homologies phénotypiques et fonctionnelles des lymphocytes B en latence III de l'EBV avec les cellules B régulatrices, implication de l'axe PD-1/PD-L1 : Study of phenotypic and functional homologies of EBV latency III B-lymphocytes with regulatory B cells, involvement of the PD-1 / PD-L1 axis.” 2017. Web. 19 Jan 2021.
Vancouver:
Auclair H. Etude des homologies phénotypiques et fonctionnelles des lymphocytes B en latence III de l'EBV avec les cellules B régulatrices, implication de l'axe PD-1/PD-L1 : Study of phenotypic and functional homologies of EBV latency III B-lymphocytes with regulatory B cells, involvement of the PD-1 / PD-L1 axis. [Internet] [Doctoral dissertation]. Limoges; 2017. [cited 2021 Jan 19].
Available from: http://www.theses.fr/2017LIMO0032.
Council of Science Editors:
Auclair H. Etude des homologies phénotypiques et fonctionnelles des lymphocytes B en latence III de l'EBV avec les cellules B régulatrices, implication de l'axe PD-1/PD-L1 : Study of phenotypic and functional homologies of EBV latency III B-lymphocytes with regulatory B cells, involvement of the PD-1 / PD-L1 axis. [Doctoral Dissertation]. Limoges; 2017. Available from: http://www.theses.fr/2017LIMO0032
Queens University
26.
Sanwalka, Daniel.
A Novel Mechanism of Tumour Cell Drug Resistance Induced by the Programmed Death-Ligand 1 (PD-L1) Immune Checkpoint
.
Degree: Biomedical and Molecular Sciences, Queens University
URL: http://hdl.handle.net/1974/24309
► Immune checkpoints are regulators of the immune system that are critical for self-tolerance and prevention of autoimmunity. The programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1)…
(more)
▼ Immune checkpoints are regulators of the immune system that are critical for self-tolerance and prevention of autoimmunity. The programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) immune checkpoint is often co-opted by tumour cells to escape the immune system. Whereas most studies on the PD-1/PD-L1 immune checkpoint focus on mechanisms leading to inactivation of immune effectors, we have shown that binding of PD-1 to PD-L1 on the surface of tumour cells leads to activation of oncogenic pathways as well as resistance to the chemotherapeutic agent doxorubicin in tumour cells. Development of drug resistance is responsible for treatment failure in over 90% of patients with metastatic cancer. Autophagy is a well-established mechanism of drug resistance in cancer cells. Hence, we hypothesized that PD-1/PD-L1 signalling induces drug resistance in tumor cells by up-regulating autophagic pathways.
Immunoblot analysis demonstrated that exposure of human breast cancer cells to recombinant PD-1 (rPD-1) resulted in a time-dependent increase in LC3-II as well as Beclin1 protein levels, two important mediators of autophagy. 4T1 mammary carcinomas from mice treated with rPD-1 also showed increased levels of LC3-II protein levels. Moreover, imaging of breast cancer cells expressing GFP-tagged LC3 revealed a time-dependent increase in autophagosome formation following administration of rPD-1. Inhibition of autophagy using chloroquine prevented drug resistance induced by PD-1/PD-L1 signalling. Furthermore, results revealed that exposure of breast cancer cells to rPD-1 resulted in increased extracellular signal-related kinase (ERK) phosphorylation, and that ERK phosphorylation is required for PD-1/PD-L1 induced autophagy. These studies provide a rationale for the use of PD-1/PD-L1 immune checkpoint blockers and autophagy inhibitors as potential chemosensitizers in cancer therapy.
Subjects/Keywords: PD-1
;
PD-L1
;
Autophagy
;
Drug Resistance
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APA ·
Chicago ·
MLA ·
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Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Sanwalka, D. (n.d.). A Novel Mechanism of Tumour Cell Drug Resistance Induced by the Programmed Death-Ligand 1 (PD-L1) Immune Checkpoint
. (Thesis). Queens University. Retrieved from http://hdl.handle.net/1974/24309
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Sanwalka, Daniel. “A Novel Mechanism of Tumour Cell Drug Resistance Induced by the Programmed Death-Ligand 1 (PD-L1) Immune Checkpoint
.” Thesis, Queens University. Accessed January 19, 2021.
http://hdl.handle.net/1974/24309.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Sanwalka, Daniel. “A Novel Mechanism of Tumour Cell Drug Resistance Induced by the Programmed Death-Ligand 1 (PD-L1) Immune Checkpoint
.” Web. 19 Jan 2021.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Vancouver:
Sanwalka D. A Novel Mechanism of Tumour Cell Drug Resistance Induced by the Programmed Death-Ligand 1 (PD-L1) Immune Checkpoint
. [Internet] [Thesis]. Queens University; [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1974/24309.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.
Council of Science Editors:
Sanwalka D. A Novel Mechanism of Tumour Cell Drug Resistance Induced by the Programmed Death-Ligand 1 (PD-L1) Immune Checkpoint
. [Thesis]. Queens University; Available from: http://hdl.handle.net/1974/24309
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.
Texas Medical Center
27.
Bartkowiak, Todd.
Novel Imaging-Based Techniques Reveal a Role for PD-1/PD-L1 in Tumor Immune Surveillance in the Lung.
Degree: MS, 2013, Texas Medical Center
URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/354
► The binding of immune inhibitory receptor Programmed Death 1 (PD-1) on T cells to its ligand PD-L1 has been implicated as a major contributor…
(more)
▼ The binding of immune inhibitory receptor Programmed Death 1 (
PD-1) on T cells to its ligand
PD-
L1 has been implicated as a major contributor to tumor induced immune suppression. Clinical trials of
PD-
L1 blockade have proven effective in unleashing therapeutic anti-tumor immune responses in a subset of patients with advanced melanoma, yet current response rates are low for reasons that remain unclear. Hypothesizing that the
PD-1/
PD-
L1 pathway regulates T cell surveillance within the tumor microenvironment, we employed intravital microscopy to investigate the in vivo impact of
PD-
L1 blocking antibody upon tumor-associated immune cell migration. However, current analytical methods of intravital dynamic microscopy data lack the ability to identify cellular targets of T cell interactions in vivo, a crucial means for discovering which interactions are modulated by therapeutic intervention. By developing novel imaging techniques that allowed us to better analyze tumor progression and T cell dynamics in the microenvironment; we were able to explore the impact of
PD-
L1 blockade upon the migratory properties of tumor-associated immune cells, including T cells and antigen presenting cells, in lung tumor progression. Our results demonstrate that early changes in tumor morphology may be indicative of responsiveness to anti-
PD-
L1 therapy. We show that immune cells in the tumor microenvironment as well as tumors themselves express
PD-
L1, but immune phenotype alone is not a predictive marker of effective anti-tumor responses. Through a novel method in which we quantify T cell interactions, we show that T cells are largely engaged in interactions with dendritic cells in the tumor microenvironment. Additionally, we show that during
PD-
L1 blockade, non-activated T cells are recruited in greater numbers into the tumor microenvironment and engage more preferentially with dendritic cells. We further show that during
PD-
L1 blockade, activated T cells engage in more confined, immune synapse-like interactions with dendritic cells, as opposed to more dynamic, kinapse-like interactions with dendritic cells when
PD-
L1 is free to bind its receptor. By advancing the contextual analysis of anti-tumor immune surveillance in vivo, this study implicates the interaction between T cells and tumor-associated dendritic cells as a possible modulator in targeting
PD-
L1 for anti-tumor immunotherapy.
Advisors/Committee Members: Tomasz Zal, Francois Claret, Eugenie Kleinerman.
Subjects/Keywords: PD-1; PD-L1; Intravital microscopy; Tumor immune surveillance; Immunotherapy; Immunoprophylaxis and Therapy; Investigative Techniques; Medicine and Health Sciences
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APA ·
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Manager
APA (6th Edition):
Bartkowiak, T. (2013). Novel Imaging-Based Techniques Reveal a Role for PD-1/PD-L1 in Tumor Immune Surveillance in the Lung. (Thesis). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/354
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Bartkowiak, Todd. “Novel Imaging-Based Techniques Reveal a Role for PD-1/PD-L1 in Tumor Immune Surveillance in the Lung.” 2013. Thesis, Texas Medical Center. Accessed January 19, 2021.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/354.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Bartkowiak, Todd. “Novel Imaging-Based Techniques Reveal a Role for PD-1/PD-L1 in Tumor Immune Surveillance in the Lung.” 2013. Web. 19 Jan 2021.
Vancouver:
Bartkowiak T. Novel Imaging-Based Techniques Reveal a Role for PD-1/PD-L1 in Tumor Immune Surveillance in the Lung. [Internet] [Thesis]. Texas Medical Center; 2013. [cited 2021 Jan 19].
Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/354.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Bartkowiak T. Novel Imaging-Based Techniques Reveal a Role for PD-1/PD-L1 in Tumor Immune Surveillance in the Lung. [Thesis]. Texas Medical Center; 2013. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/354
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
28.
Raffo Iraolagoitia, Ximena Lucía.
Rol de las células NK en el desarrollo de la respuesta inmune adaptativa mediada por LT CD8 contra antígenos tumorales.
Degree: Farmacia y Bioquímica, 2016, Universidad de Buenos Aires
URL: http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgrauba&cl=CL1&d=HWA_1161
;
http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgrauba/index/assoc/HWA_1161.dir/1161.PDF
► Despite the classical function of NK cells in the elimination of tumors, evidence for a regulatory role for NK cells has been emerging in different…
(more)
▼ Despite the classical function of NK cells in the elimination of tumors, evidence for a regulatory role for NK cells has been emerging in different models. However, this role has not been fully explored in the context of a growing tumor. In this thesis work, we show that NK cells can limit spontaneous cross-priming of tumor antigen-specific CD8 T cells, leading to reduced memory responses. After challenge with MC57.SIY cells, NK cell-depleted mice exhibited a higher frequency of SIY-specific CD8 T cells, with enhanced effector functions. Depletion of NK cells resulted in a CD8 T cell population skewed towards an effector-memory T phenotype which was associated with enhanced recall responses and delayed tumor growth after a secondary tumor challenge with B16.SIY cells. Mechanistically, we found that tumor-primed NK cells displayed an up-regulated expression of the inhibitory molecule PD-L1 and, through interaction with PD-1 expressed on DC, limited DC activation, explaining their reduced ability to induce tumor-specific CD8 T cell priming. Our results suggest that NK cells can, in certain contexts, have an inhibitory effect on anti-tumor immunity, a finding with implications for immunotherapy in the clinic.
Fil: Raffo Iraolagoitía, Ximena Lucía. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Si bien las células NK son tradicionalmente estudiadas por sus funciones anti-tumorales, recientes evidencias destacan su rol regulatorio en diferentes modelos. Sin embargo, este rol no fue aún explorado en el contexto de un tumor en crecimiento. En este trabajo de tesis demostramos que las células NK limitan la expansión y activación de LT CD8 anti-tumorales, conduciendo a respuestas de memoria menos eficientes. Luego del desafío con células MC57.SIY, los ratones depletados de células NK en comparación con los ratones control, presentaron una mayor expansión de LT CD8 anti-SIY junto con un aumento en las funciones efectoras de los LT CD8 y un mayor porcentaje de LT CD8 de memoria efectora. Estos ratones, al ser re-desafiados con células B16.SIY, desarrollaron una respuesta inmune de memoria más eficiente acompañada de un retraso en el crecimiento del tumor secundario. Mecanísticamente, encontramos que las células NK activadas en el microambiente tumoral expresan elevados niveles de PD-L1 y, a través de interacciones con PD-1 en las DCs, limitan su maduración, conduciendo a una menor activación de los LT CD8 anti-tumorales. Nuestros resultados sugieren que las células NK pueden tener una actividad regulatoria sobre la inmunidad anti-tumoral, constituyendo un aporte para el diseño de inmunoterapias.
Advisors/Committee Members: Hajos, Silvia, Fuertes, Mercedes Beatriz, Baldi, Pablo, Sasiain, María del Carmen, Fainboim, Leonardo.
Subjects/Keywords: Células NK; LT CD8; DCs; PD-1/PD-L1; Inmunidad anti-tumoral; Ciencia de la vida
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Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Raffo Iraolagoitia, X. L. (2016). Rol de las células NK en el desarrollo de la respuesta inmune adaptativa mediada por LT CD8 contra antígenos tumorales. (Thesis). Universidad de Buenos Aires. Retrieved from http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgrauba&cl=CL1&d=HWA_1161 ; http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgrauba/index/assoc/HWA_1161.dir/1161.PDF
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Raffo Iraolagoitia, Ximena Lucía. “Rol de las células NK en el desarrollo de la respuesta inmune adaptativa mediada por LT CD8 contra antígenos tumorales.” 2016. Thesis, Universidad de Buenos Aires. Accessed January 19, 2021.
http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgrauba&cl=CL1&d=HWA_1161 ; http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgrauba/index/assoc/HWA_1161.dir/1161.PDF.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Raffo Iraolagoitia, Ximena Lucía. “Rol de las células NK en el desarrollo de la respuesta inmune adaptativa mediada por LT CD8 contra antígenos tumorales.” 2016. Web. 19 Jan 2021.
Vancouver:
Raffo Iraolagoitia XL. Rol de las células NK en el desarrollo de la respuesta inmune adaptativa mediada por LT CD8 contra antígenos tumorales. [Internet] [Thesis]. Universidad de Buenos Aires; 2016. [cited 2021 Jan 19].
Available from: http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgrauba&cl=CL1&d=HWA_1161 ; http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgrauba/index/assoc/HWA_1161.dir/1161.PDF.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Raffo Iraolagoitia XL. Rol de las células NK en el desarrollo de la respuesta inmune adaptativa mediada por LT CD8 contra antígenos tumorales. [Thesis]. Universidad de Buenos Aires; 2016. Available from: http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgrauba&cl=CL1&d=HWA_1161 ; http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgrauba/index/assoc/HWA_1161.dir/1161.PDF
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Universitat Autònoma de Barcelona
29.
Bassas Freixas, Patricia.
Caracterización de la expresión de ácido ribonucleico mensajero en distintos subtipos histológicos de carcinoma basocelular.
Degree: Departament de Medicina i Cirurgia Animals, 2018, Universitat Autònoma de Barcelona
URL: http://hdl.handle.net/10803/665811
► Basal cell carcinomas (BCC) are the most common cancers worldwide and their incidence is increasing annualy. A subset of BCC behaves more aggressively and are…
(more)
▼ Basal cell carcinomas (BCC) are the most common cancers worldwide and their incidence is increasing annualy. A subset of BCC behaves more aggressively and are associated with a higher risk of recurrence, local tissue destruction, deeper invasion, subclinical spread, morbidity and distant metastasis risk. The molecular basis for the aggressive behavior, for the different clinical and pathological forms of BCC and their response to the treatments available remains to be elucidated. In this study we evaluated 25 BCC (superficial, nodular, morpheaform and infiltrative) to delineate their molecular heterogeneity by means of mRNA expression analysis. We identified 120 immune-related genes linked to immune response with high expression in most of infiltrative CBC, medium expression in superficial CBC and low in morpheaform and nodular. To corroborate these findings we analyzed these 120 genes and discovered that
PD-
L1 expression was associated with infiltrative BCC samples compared to nodular, superficial, morpheaform and basosquamous BCC (p=0,01). Overall, our results suggest that the
PD-1/
PD-
L1 axis may play an important role in locally infiltrative BCC and provide support for
PD-1/
PD-
L1 blockade.
Advisors/Committee Members: [email protected] (authoremail), true (authoremailshow), García-Patos Briones, Vicente (director), Prat Aparicio, Aleix (director).
Subjects/Keywords: Carcinoma basocel·lular; Carcinoma basocelular; Basal cell carcinoma; Pd-1; PD-L1; RNA-sequencing; Ciències de la Salut; 616.5
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APA (6th Edition):
Bassas Freixas, P. (2018). Caracterización de la expresión de ácido ribonucleico mensajero en distintos subtipos histológicos de carcinoma basocelular. (Thesis). Universitat Autònoma de Barcelona. Retrieved from http://hdl.handle.net/10803/665811
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Bassas Freixas, Patricia. “Caracterización de la expresión de ácido ribonucleico mensajero en distintos subtipos histológicos de carcinoma basocelular.” 2018. Thesis, Universitat Autònoma de Barcelona. Accessed January 19, 2021.
http://hdl.handle.net/10803/665811.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Bassas Freixas, Patricia. “Caracterización de la expresión de ácido ribonucleico mensajero en distintos subtipos histológicos de carcinoma basocelular.” 2018. Web. 19 Jan 2021.
Vancouver:
Bassas Freixas P. Caracterización de la expresión de ácido ribonucleico mensajero en distintos subtipos histológicos de carcinoma basocelular. [Internet] [Thesis]. Universitat Autònoma de Barcelona; 2018. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/10803/665811.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Bassas Freixas P. Caracterización de la expresión de ácido ribonucleico mensajero en distintos subtipos histológicos de carcinoma basocelular. [Thesis]. Universitat Autònoma de Barcelona; 2018. Available from: http://hdl.handle.net/10803/665811
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Manchester
30.
Oguejiofor, Kenneth Kenechukwu.
Prognostic markers in oropharyngeal cancers.
Degree: PhD, 2016, University of Manchester
URL: https://www.research.manchester.ac.uk/portal/en/theses/prognostic-markers-in-oropharyngeal-cancers(fda96224-657d-4049-ae6c-50db33a5388a).html
;
http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.684833
► Introduction: Human papillomavirus (HPV) is changing the prevalence, survival and treatment paradigms in oropharyngeal squamous cell carcinoma (OPSCC). Improved survival of patients with HPV positive…
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▼ Introduction: Human papillomavirus (HPV) is changing the prevalence, survival and treatment paradigms in oropharyngeal squamous cell carcinoma (OPSCC). Improved survival of patients with HPV positive compared to HPV negative OPSCC has led to trials of treatment de-escalation. Current HPV detection methods are imprecise, therefore standardised assessment of transcriptionally active HPV in OPSCC is required. Furthermore, the differences in immune characteristics and/or the hypoxia response/effects could explain observed differences in prognosis between HPV positive and negative OPSCC. Rigorous HPV detection and subsequent biomarker evaluation should provide additional information required before introduction of treatment de-escalation in broad patient groupings. Methods: The study cohort was 218 patients with OPSCC who received radiotherapy with curative intent. HPV status was determined on pre-treatment, formalin-fixed paraffin-embedded blocks using: 1) polymerase chain reaction (PCR); 2) in-situ hybridisation (ISH) and 3) immuno-histochemistry (IHC). QuantiGene multiplex assay was designed to detect mRNA of reference sequences of the common high-risk HPV types (16, 18, 33, 35, 45, 52 and 58). HPV detection methods were compared with mRNA quantification. Multimarker IHC of immune cell markers using chromogenic and fluorescent staining was performed, analysed and compared with single marker IHC using automated multispectral image analysis. A validated multiplex IHC method was used for a) chromogenic (CD3, CD4, CD8, and FoxP3) and b) fluorescent (CD8, CD68 and PD1/PD-L1) evaluation in tumour and stroma compartments. Single marker IHC was used to investigate tumour hypoxia markers (HIF-1α and CA-IX) in HPV positive and negative OPSCC. Results: p16 IHC and ISH were the most sensitive and specific, respectively, for classifying HPV status. The combination of the three tests had the highest positive/negative predictive values compared with QuantiGene mRNA detection. Multiplex validation showed that, for serial sections up to 6 μm apart, there were highly significant correlations (P<0.0001) between single and multiplex counts for both chromogenic and fluorescent IHC. Overall there was less variation in cell counts with fluorescent staining when compared to chromogenic staining. Multiplex IHC of TILs in HPV positive and negative OPSCC showed higher infiltration in both tumour and stromal areas of CD3+CD4+ and CD3+CD8+ T cells but not CD4+FoxP3 Tregs in HPV positive compared with HPV negative OPSCC. Only CD3+CD8+ stromal and not tumour area infiltration was associated with increased survival (P=0.02). PD-L1 expression was higher in HPV negative OPSCC and this was related to macrophage (CD68) expression of PD-L1. In HPV negative tumours infiltration with CD68+PD-L1 was associated with a good prognosis. HPV negative patients had higher expression of HIF-1α but not CA-IX. High expression of both markers was associated with a poor prognosis irrespective of HPV status. Conclusions: There are other prognostic factors operating in…
Subjects/Keywords: 616.99; Oropharyngeal cancers (OPSCC); Human papilloma virus (HPV); Tumour infiltrating lymphocytes (TIL); Hypoxia; PD-1/PD-L1; Multiplex immunohistochemistry
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APA (6th Edition):
Oguejiofor, K. K. (2016). Prognostic markers in oropharyngeal cancers. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/prognostic-markers-in-oropharyngeal-cancers(fda96224-657d-4049-ae6c-50db33a5388a).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.684833
Chicago Manual of Style (16th Edition):
Oguejiofor, Kenneth Kenechukwu. “Prognostic markers in oropharyngeal cancers.” 2016. Doctoral Dissertation, University of Manchester. Accessed January 19, 2021.
https://www.research.manchester.ac.uk/portal/en/theses/prognostic-markers-in-oropharyngeal-cancers(fda96224-657d-4049-ae6c-50db33a5388a).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.684833.
MLA Handbook (7th Edition):
Oguejiofor, Kenneth Kenechukwu. “Prognostic markers in oropharyngeal cancers.” 2016. Web. 19 Jan 2021.
Vancouver:
Oguejiofor KK. Prognostic markers in oropharyngeal cancers. [Internet] [Doctoral dissertation]. University of Manchester; 2016. [cited 2021 Jan 19].
Available from: https://www.research.manchester.ac.uk/portal/en/theses/prognostic-markers-in-oropharyngeal-cancers(fda96224-657d-4049-ae6c-50db33a5388a).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.684833.
Council of Science Editors:
Oguejiofor KK. Prognostic markers in oropharyngeal cancers. [Doctoral Dissertation]. University of Manchester; 2016. Available from: https://www.research.manchester.ac.uk/portal/en/theses/prognostic-markers-in-oropharyngeal-cancers(fda96224-657d-4049-ae6c-50db33a5388a).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.684833
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