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

Highly coordinated changes in gene expression underlie T cell 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 T cell 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 T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.
Competing Interests: Declaration of interests C.K. is the scientific founder, scientific advisor to the board of directors, scientific advisory board member, shareholder, and consultant for Foghorn Therapeutics, Inc. (Cambridge, MA). C.K. is also a member of the scientific advisory board and is a shareholder of Nested Therapeutics and Nereid Therapeutics, serves on the scientific advisory board for Fibrogen, Inc. and on the Molecular Cell editorial board, and is a consultant for Cell Signaling Technologies and Google Ventures. I.A. is a scientific consultant for Foresite Labs and receives research funding from AstraZeneca Inc. F.P. is an inventor on patents related to adoptive cell therapies, held by MSKCC (some licensed to Takeda), serves as a consultant for AstraZeneca, and receives research support from Lonza and NGMBio. A.T. is a scientific advisor to Intelligencia AI.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)