Abstract LB321: ACTL6A (SWI/SNF complex subunit) cooperates with EZH2 and maintains a repressive chromatin state to modulate a immune COLD phenotype in squamous cancers

Abstract Squamous cell carcinoma of the head and neck (HNSCC) is a common cancer worldwide with the overall survival rate for patients with HNSCC at 50%. Hippo pathway is altered in 50% of head and neck cancers. Amplification of the SWI/SNF chromatin remodeling factor ACTL6A/BAF53a gene is observed in 20% of HNSCCs and is associated with poor clinical outcomes. However, the mechanisms by which ACTL6A contributes to HNSCC remain unknown. Here, we demonstrate that overexpressed ACTL6A mediates transcriptional repression of a tumor cell-intrinsic immune response program including antigen presentation machinery and chemotactic cytokine genes. Our prior studies have shown that ACTL6A and Hippo pathway collaborate to drive HNSCC. Detailed analysis of this pathway reveals mechanisms by which tumor cell-intrinsic immune response program is inhibited including antigen presentation machinery and chemotactic cytokine genes. We uncover the direct molecular mechanism of ACTL6A-mediated repression, revealing that high-level ACLT6A induces an unanticipated increase in EZH2 chromatin binding and H3K27 tri-methyl deposition, and we show that clinical EZH2 inhibitors mimic the gene expression changes and physiologic effects of ACTL6A loss. Utilizing single cell RNA and single cell ATAC approaches in head and neck, and skin squamous cancer patient tumors that are surgically removed, we uncover the chromatin state indicative of a COLD tumor phenotype and contributing to cellular plasticity and tumor heterogeneity. Conclusively, we identify a therapeutically targetable epigenetic program for immune evasion in head and neck cancers. Citation Format: SrinivasVinod Saladi, Nana Chen. ACTL6A (SWI/SNF complex subunit) cooperates with EZH2 and maintains a repressive chromatin state to modulate a immune COLD phenotype in squamous cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB321.