Role of STAT1 in Disease Progression and the Tumour Immune Microenvironment of High-Grade Serous Ovarian Cancer
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Authors
Reid-Schachter, Gillian
Date
Type
thesis
Language
eng
Keyword
Ovarian Cancer , Tumour Microenvironment , Immunoreactive , Chemoresistance , Tumour Infiltrating Lymphocytes , STAT1
Alternative Title
Abstract
Ovarian high-grade serous carcinomas (HGSC) are the most common and fatal histological subtype of ovarian cancer, characterised by late stage diagnosis and high mortality rates. Unfortunately, the majority of patients (> 85%) will develop fatal chemoresistant disease despite multiple lines of treatment. Recent studies investigating the tumour immune microenvironment have highlighted the prognostic significance of different tumour infiltrating lymphocyte (TIL) subsets and secreted immune factors in HGSC. However, the mechanisms promoting TIL recruitment to the tumour epithelial compartment, where they show the most benefit, remain poorly understood in HGSC. It is known that alterations and activities of TILs are mediated by the interaction of various cytokines and growth factors in the tumour microenvironment (TME). Signal transducer and activator of transcription 1 (STAT1) is activated in response to interferon signalling and upregulates cytokines responsible for the recruitment of TILs to the TME. Building on previous findings linking STAT1 expression to a pre-existing immunoreactive TME and improved clinical outcome in HGSC, the current study investigates the role of cancer cell intrinsic STAT1 expression in regulating an anti-tumour immune microenvironment and disease progression in HGSC. Immune transcriptomic analysis of HGSC patient tumours indicates a significant downregulation of immune related genes in chemoresistant patients with low-STAT1 expression. Functional studies confirmed STAT1 as a positive regulator of anti-tumour immune responses in the TME through its role in cytokine signalling and TIL recruitment. In vitro experiments revealed that decreased STAT1 expression is associated with increased cancer cell proliferation, invasion and migration. In vivo experiments in a syngeneic mouse model of HGSC revealed that decreased STAT1 in the TME increased disease burden and led to decreased infiltration of CD8+ TILs. These findings are important for the design of immune based therapies to improve chemotherapy response and overall survival in HGSC patients. Further work is required to identify appropriate immunotherapy and chemotherapy combinations for HGSC patients based on their immune profiles.
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Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This 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.