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dc.contributor.authorSanwalka, Daniel
dc.contributor.otherQueen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))en
dc.date.accessioned2018-07-12T18:12:48Z
dc.date.available2018-07-12T18:12:48Z
dc.identifier.urihttp://hdl.handle.net/1974/24309
dc.description.abstractImmune 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.en_US
dc.language.isoenen_US
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectPD-1en_US
dc.subjectPD-L1en_US
dc.subjectAutophagyen_US
dc.subjectDrug Resistanceen_US
dc.titleA Novel Mechanism of Tumour Cell Drug Resistance Induced by the Programmed Death-Ligand 1 (PD-L1) Immune Checkpointen_US
dc.typethesisen
dc.description.degreeMaster of Scienceen_US
dc.contributor.supervisorGraham, Charles
dc.contributor.departmentBiomedical and Molecular Sciencesen_US
dc.embargo.termsI wish to have the thesis restricted. This is because we have not yet publically published these data and must keep it private until we publish it. Dr. Graham will confirm via email.en_US
dc.embargo.liftdate2023-07-12T17:27:33Z


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