Defining oncogenic SWI/SNF complex mediated immune reprogramming in squamous cell carcinoma

Squamous cell carcinoma (SCC) remains among the most treatment-refractory of human cancers, reflecting in part a limited understanding of the key pathways and mechanisms that drive this disease. The p53-related transcription factor p63 is a central tumor maintenance factor subject to overexpression and/or genomic amplification in a high fraction of SCCs. Loss-of-function mutations in SWI/SNF chromatin remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. We reveal that ACTL6A, encoding a SWI/SNF subunit linked to stem and progenitor cell function, is frequently co-amplified and highly expressed together with p63 in head and neck, and lung squamous cell carcinoma (HNSCC & LUSC). ACTL6A and p63 physically interact and cooperatively control a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1. Consequently, loss of ACTL6A or p63 in tumor cells induces YAP phosphorylation and inactivation, associated with growth arrest and terminal differentiation, all phenocopied by WWC1 overexpression. In vivo, ectopic ACTLC6A/p63 expression promotes tumorigenesis, while ACTL6A expression and YAP activation are highly correlated in primary HNSCC and predict poor patient survival. More recently, we show the major cell-autonomous pathway repressed by ACTL6A is the interferon response in vitro, while we find ACTL6A amplification in HNSCC is associated with immunologically “cold” tumors despite a high mutation burden in vivo. Collectively, these findings reveal that ACTL6A orchestrates a tumor cell-intrinsic mechanism of immune evasion and define ACTL6A as a potent driver of human SCC.These findings establish a fundamental mechanism for ACTL6A and p63 to alter epigenetic states, and uncover a critical oncogenic function for SWI/SNF, which has been largely viewed as a tumor suppressor in human cancer. Furthermore, by revealing the Hippo-YAP pathway as a major target of ACTL6A/p63 linked to tumor behavior, this work suggests potential therapeutic approaches for refractory HNSCC cases. Citation Format: SrinivasVinod Saladi, Robert Morris, Kenneth Ross, mihriban Karaayvaz, Purushothama Rao Tata, hongmei mou, Jayaraj Rajagopal, Michael Lawrence, Leif Ellisen. Defining oncogenic SWI/SNF complex mediated immune reprogramming in squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-103.