Abstract 1521: Chromatin remodeler ACTL6A in CD8+ T cells promotes antitumor immunity

Abstract Chromatin remodeling plays a pivotal role in dictating epigenetic and transcriptomic regulation governing cytotoxic T lymphocyte differentiation and effector function. However, the regulatory mechanisms underlying chromatin remodeler assembly and actions remains unclear. Actin-like gene family members have been implicated in the organization of chromatin landscapes, however their role in T cell functional regulation remains unknown. We identified Actin-like protein 6A/Actl6a as the most upregulated gene within actin-like family members upon CD8+ T cell activation across multiple species. Additionally, ACTL6A is highly expressed in human tumor-infiltrating CD8+ mitotic tissue-resident memory T cells, suggesting a functional importance of ACTL6A in this subset. Deletion of mouse Actl6a in mature T lymphocytes impairs immune responses to transplanted syngeneic mouse tumors. T cell-specific Actl6a deletion mice exhibit a reduced effector memory population and attenuated cytotoxicity in their tumor infiltrating CD8+ T cells. Heterozygous deletion of Actl6a displays an intermediate reduction of effector memory population and cytotoxicity between that of wildtype and homozygous knockout, indicating that ACTL6A acts in a dose-dependent manner to promote CD8+ effector cell fate. T cell adoptive transfer further corroborates a CD8+ T cell-intrinsic role of Actl6a on antitumor adaptive immunity. Currently, we are investigating the chromatin landscape and transcriptomic changes upon loss of Actl6a using ATAC-seq and RNA-seq. Furthermore, the dose dependency of Aclt6a on CD8+ T cell effector function suggests that pharmacological or genetic approaches to increase Actl6a expression in CD8+ T cells may have the potential to boost immune based anticancer therapies including CAR-T therapies. Citation Format: Bogang Wu, Win Thant, Elena Bitman, Ting Liu, Leif W. Ellisen. Chromatin remodeler ACTL6A in CD8+ T cells promotes antitumor immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1521.