Abstract A004: Modulating chromatin remodeling as a strategy to reverse immune evasion in ovarian cancer

Abstract Ovarian cancer (OC) has an immunosuppressed tumor microenvironment (TME) with poor responses to immune checkpoint blockade (ICB). Understanding tumor immune-cell interactions is critical to overcome barriers to ICB. There is growing evidence that the chromatin remodeler complex, mammalian switch/sucrose non-fermentable (mSWI/SNF) affects downstream immune pathways in cancer. Our previous study has shown that loss-of-function as well as therapeutic inhibition of the mSWI/SNF subunit, SMARCA4, leads to increased immunogenicity in vitro and in vivo. We found that SMARCA4 loss in OC cell lines leads to increased MHC1 antigen presentation and upregulation of interferon (IFN) signaling pathway, including IFN-stimulated genes (ISGs) and RNA sensors involved in the anti-viral RNA sensing pathway. Our in vivo results show anti-tumor immune suppression of SMARCA4-KO OC tumors, resulting from a more active innate and adaptive immune TME. We further demonstrate that therapeutic targeting of SMARCA4 gene product BRG1 can recapitulate these findings in vitro and in vivo. An epigenetic library screen of SMARCA4-mutated OC cells revealed DNA methyltransferase (DNMT) as a top hit. There is evidence that therapeutic inhibition of this target may synergize in the context of SMARCA4 inhibition by activating ISGs through increased gene accessibility and transcription from decreased histone methylation. Based on our previous data, we hypothesize that combination of BRG1 inhibitor (BRG1i) and DNMT inhibition can reverse immune evasion in the OC TME and sensitize OCs to ICB. Using murine syngeneic and human OC cell lines, the expression of type I IFN and antigen presentation genes are characterized in vitro to demonstrate the immunogenic effect of dual epigenetic therapy. Combined BRG1 and DNMT1 inhibition in murine OC cells ID8 TP53-/- results in an increased fold change of ISG expression by RT-qPCR when compared to monotherapy. These results were validated in the human OC cells. Furthermore, combination therapy in murine and human cells increases the expression of antigen presentation marker MHC1 at the cells surface. In vivo, we observed a trend towards decreased tumor burden and the prevention of ascites development with dual epitherapy. Immune cell infiltration and activation in the TME will be subsequently investigated. Moreover, in an ongoing pilot study the anti-tumor response to anti-PD1 ICB combined with both epitherapies yields decreased tumor growth compared to both anti-PD1 alone and dual therapy alone. Taken together, these data uncover potential therapeutically innovative ways to exploit functional characteristics of epigenetic modulation and are immediately relevant to the design of next generation OC therapeutics. Citation Format: Olivia Mckeeman, Maroua Mbarik, Amber Yasmeen, Angela Tatar, Walter Gotlieb, Melica Brodeur. Modulating chromatin remodeling as a strategy to reverse immune evasion in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr A004.