Chromatin Remodeling Factors Drive Epigenetic Changes Crucial for T-cell Exhaustion

Chronic T-cell stimulation promotes T-cell exhaustion and reduced immunotherapy efficacy as well as global changes to the transcriptome and epigenome; however, the factors that drive this transformation remain undetermined. By performing a genome-wide CRISPR screen in an in vitro model of T-cell exhaustion that recapitulates in vivo transformations, Belk and colleagues identified the chromatin remodeling complexes cBAF and INO80 as critical genetic regulators of T-cell exhaustion. An in vivo CRISPR screen (limited to the top 300 hits of the in vitro genome-wide screen) in two murine models also showed consistent results with perturbations of cBAF and INO80 chromatin remodelers preventing T-cell exhaustion in response to chronic antigen stimulation. Functional assays revealed that blocking T-cell exhaustion by depleting subunits of the cBAF complex improves T-cell antitumor activity in vivo, and genetic ablation of the cBAF component ARID1A in primary human CD8⁺ T cells increases viability, persistence, and antitumor activity. In order to understand the molecular mechanism driving improved T-cell function, a limited single-guide RNA pool targeting INO80 and BAF complex components was generated and showed, using Perturb-seq on in vivo murine T-cell populations, that cBAF and INO80 complexes were found to have distinct transcriptional roles in T-cell exhaustion. Targeting cBAF subunits Arid1a, Smarcd2, and Smarcc1 induced shared gene expression changes, including an increase in effector molecules Gzmb and Ifng and a global enrichment in T-cell activation programs, while targeting INO80 complex members significantly altered metabolism-related genes. Assay for transposase-accessible chromatin with high-throughput sequencing following ARID1A knockout in both murine and primary human CD8⁺ T cells further exhibited a global decrease in accessibility of genomic regions unique to chronic stimulation, with the epigenome of these ARID1A knockout cells being more similar to naïve and activated T-cell populations. In summary, this study demonstrates that cBAF and INO80 complexes epigenetically dictate T-cell exhaustion in response to chronic stimulation and suggests improvement can be made to cancer immunotherapies through modulation of this epigenetic state.

Belk JA, Yao W, Ly N, Freitas KA, Chen YT, Shi Q, et al. Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence. Cancer Cell 2022;40:768–86.e7.

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