Abstract 1599: SMARCA4 regulates tumor resistance to anti-tumor immune response

Abstract

Abstract Chromatin remodelers regulate chromatin accessibility and translocation of the nucleosome to expose the underlying DNA sequence. SWI/SNF is a conserved chromatin remodeling complex required for transcriptional activation or repression. In fact, SWI/SNF is the most frequently mutated chromatin regulator in cancer. Though the general understanding is that subunits of the SWI/SNF complex mainly act as tumor suppressors, studies have shown that they can have a context-dependent oncogenic role. Moreover, the PBAF subunits of the complex, PBRM1 and ARID2 impart immunoresistance in B16 melanoma tumors. We perform a TCGA analysis of the subunits based on expression and see that high PBRM1 or SMARCA4 expression in SKCM melanoma correlates with lower survival. Interestingly, SMARCA4 is the conserved catalytic subunit of the complex, and is essential to hydrolyze the energy of the ATP to execute the remodeling function of the complex. On performing a knockdown of SMARCA4 in an in vitro model of B16 cells, a co-culture with antigen specific T cells shows an increase in T cell cytotoxicity. Furthermore, RNA sequencing reveals that knockdown of SMARCA4 upregulates the genes associated with interferon response and downregulates MYC targets. We show that SMARCA4 may mediate immunoresistance such that a knockdown of SMARCA4 in the tumor will sensitize it to anti-tumor immunity. We will next take an in vivo approach to examine if SMARCA4 knockdown will enhance the tumor immune response via an interferon related mechanism. Citation Format: Apoorvi Chaudhri, Yunfei Wang, Leilei Shi, Kunal Rai, Patrick Hwu. SMARCA4 regulates tumor resistance to anti-tumor immune response [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 1599.