Abstract 1708: Improving genotype specific chemotherapy response in ovarian cancer via cGAS-STING pathway activation

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 (IFN) 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 therapy through a heightened type 1 IFN (IFN1) response. 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 (~25% of HGSC cases) have higher CD8+ T cell infiltration in contrast to those with loss of PTEN (~10% of cases). 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 through local and systemic immune profiling. The addition of 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 inform rational combinations of STING pathway activating therapies in HGSC, augmenting responses to existing chemotherapy regimens and prolonging survival rates in patients. Citation Format: Noor Shakfa, Elizabeth Lightbody, Deyang Li, Juliette Wilson-Sanchez, Gwenaelle Conseil, Afrakoma Afriyie-Asante, Stephen Chenard, Ali Hamade, Madhuri Koti. Improving genotype specific chemotherapy response in ovarian cancer via cGAS-STING pathway activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1708.