Genomic correlates of the tumor immune microenvironment and response to therapeutic STING pathway activation in high grade serous ovarian carcinoma
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Authors
Shakfa, Noor
Date
Type
thesis
Language
eng
Keyword
ovarian cancer , STING pathway , tumor immune microenvironment , genotype , genetic alterations
Alternative Title
Abstract
High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy, characterized by late diagnosis and high rates of recurrence. While most patients show initial sensitivity to platinum-taxane based chemotherapy, >80% relapse. The vast tumor immune and genetic heterogeneity pose challenges in our understanding of their response to therapy. Emerging evidence suggests cancer cell intrinsic genetic alterations influence the tumor immune microenvironment (TIME) and treatment response. Although TP53 is a universal mutation in HGSC, mutations in BRCA1, BRCA2, NF1 and PTEN also occur frequently, where tumors with the loss of DNA damage repair genes such as BRCA1/2 exhibit higher CD8+ cytotoxic T cell infiltration, chemosensitivity and favorable prognosis. However, immune states associated with mutations in NF1 and PTEN have not been fully characterized. The central theme of this research was to investigate the effect of cancer cell genetic alterations on interferon (IFN) activity and the associated tumor immune milieu. We specifically explored this in the context of cytosolic innate sensing cGAS-Stimulator of Interferon Genes (STING) pathway, establishing the potential of re-sensitizing tumors with a suppressed TIME via exogenous STING pathway activation.
Our findings validate the immune heterogeneity in human HGSC tumors and report the prognostic relevance of immune checkpoints programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), which was dependent on their localization. Higher epithelial PD-1 and stromal PD-L1 associated with longer disease specific survival. Next, we illustrated genotype-specific differences in IFN-1 gene signatures, the associated TIME and overall survival outcomes using Trp53, Brca1, Brca2, Nf1 and Pten mutations in the ID8 syngeneic murine model of HGSC. Differences in immune profiles of various metastatic sites was observed, with tumors along the uterine horn displaying significantly higher immune infiltration compared to those from peritoneal metastases. Lastly, we identified that Pten deficient ovarian cancer cells establish an immunosuppressed TIME driven by macrophage dominance in the malignant ascites. Exogenous STING pathway activation in mice injected with ID8-Trp53-/-; Pten-/- cells enhanced the sensitivity of tumors to chemotherapy and increased overall survival outcomes. STING pathway activation reprogrammed intraperitoneal M2-like macrophages into an M1-like phenotype and rescued CD8+ cytotoxic T cell activation. Overall, this thesis corroborates the immune heterogeneity observed in HGSC and identifies the importance of considering the influence of cancer cell intrinsic genetic alterations on the TIME state and therapeutic selection for combination therapies activating the STING pathway.
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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.