STING pathway mediated immunologic consequences of DNA damage repair gene losses in high-grade serous ovarian tumors

Abstract

Abstract High grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy with high rates of chemotherapy resistance and poor outcomes. Our previous studies have demonstrated the variable tumor immune microenvironment states that associate with platinum chemotherapy response. We further showed the significance of the interferon induced chemokine CXCL10 as a key mediator of tumor infiltrating immune cell recruitment. Using the ID8-Trp53−/− murine model of HGSC, we demonstrated the potential of Stimulator of Interferon Genes (STING) pathway activation in enhancing response of HGSC tumors to carboplatin chemotherapy and sensitizing them to immune checkpoint blockade. Notably, CXCL10 production via IFN1 is also governed by genes that regulate cellular DNA damage repair pathways. Evolving evidence indicates a role of BRCA1 and PTEN genes in mediating cellular IFN1 responses. Losses in the function of these genes is widely prevalent in a large proportion of HGSC tumors, where tumors with BRCA1 mutations have higher CD8+ T cell infiltration in contrast to those with loss of PTEN. We hypothesized that HGSC tumors with loss of PTEN expression can be rendered susceptible to immune mediated killing via activating the STING pathway. Tumors generated from ID8-Trp53−/−; Brca1−/− cells and those from ID8-Trp53−/−; Pten−/− cells in C57BL6 mice showed significant immunologic differences. STING agonist treatment significantly increased chemosensitivity and improved overall response in mice implanted with ID8-Trp53−/−; Pten−/− cells compared to those treated with carboplatin alone, altering immune responses. This study is foundational to guide rationalistic combinations of STING pathway activating therapies in HGSC.