Interferon response and epigenetic modulation by <i>SMARCA4</i> mutations drive ovarian tumor immunogenicity.

Abstract

Cell-intrinsic mechanisms of immunogenicity in ovarian cancer (OC) are not well understood. Damaging mutations in the SWI/SNF chromatin remodeling complex, such as <i>SMARCA4</i> (BRG1), are associated with improved response to immune checkpoint blockade; however, the mechanism by which this occurs is unclear. We found that <i>SMARCA4</i> loss in OC models resulted in increased cancer cell-intrinsic immunogenicity, characterized by up-regulation of long-terminal RNA repeats, increased expression of interferon-stimulated genes, and up-regulation of antigen presentation machinery. Notably, this response was dependent on STING, MAVS, and IRF3 signaling but was independent of the type I interferon receptor. Mouse ovarian and melanoma tumors with <i>SMARCA4</i> loss demonstrated increased infiltration and activation of cytotoxic T cells, NK cells, and myeloid cells in the tumor microenvironment. These results were recapitulated in BRG1 inhibitor-treated <i>SMARCA4-</i>proficient tumor models, suggesting that modulation of chromatin remodeling through targeting <i>SMARCA4</i> may serve as a strategy to overcome cancer immune evasion.