Chromatin remodeler ACTL6A in CD8⁺ T cells promotes antitumor immunity

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. T cell adoptive transfer further corroborates a CD8⁺ T cell-intrinsic role of Actl6a on antitumor adaptive immunity. Transcriptomic/epigenetic investigations provide mechanistic insights into the action of ACTL6 in the CD8⁺ T cells regulation. Furthermore, our study 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.