Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion

Abstract

Highly coordinated changes in gene expression underlie Tcell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic Tcell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of Tcells with attenuated exhaustion hallmarks and increased memory features invitro and invivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control invivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of Tcell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.