Low expression of cBAF components and MYC support a pro–memory CD8+ T-cell fate decision.

  • Major Finding: Low expression of cBAF components and MYC support a pro–memory CD8+ T-cell fate decision.

  • Concept: The chromatin landscape of activated CD8+ T cells is established by cBAF complex and MYC interactions.

  • Impact: Early manipulation of cBAF in CD8+ T-cell activation can improve cancer immunotherapy efficacy.

Memory T cells (Tmem) have an important role in supporting the function of anticancer immunotherapy; however, the mechanisms behind their generation remain undetermined. Using a CRISPR screen to identify negative regulators of Tmem generation, Guo, Huang, and colleagues showed that deletion of cBAF complex components promoted memory precursor (MP) versus terminal effector (TE) CD8+ T cells. The CRISPR screen also noted an enrichment of single-guide RNA (sgRNA) targeting Myc in MP cells. MYC and cBAF components often assorted together and asymmetrically in dividing T cells, and MYClo daughter cells demonstrated reduced chromatin accessibility and enhanced Tmem cell function. Knockout of ARID1A expression (a cBAF-specific component) in both MYChi and MYClo cells also promoted an MP-cell phenotype, supporting the need for cBAF in determining MYC expression–dependent T-cell fate decisions. Investigation into functional interactions between cBAF components and MYC revealed coprecipitation of ARID1A with MYC in activated CD8+ T cells as well as MYC occupation on 45% of ARID1A-binding sites leading to promotion of MYC target gene sets and gene sets involved in T-cell activation and differentiation. Furthermore, ARID1A-deficient T cells exhibited a reduction in MYC binding sites, including those involved in effector T-cell differentiation and function. MYC-deficient T cells showed reduced ARID1A and BRG1 chromatin binding, suggesting that MYC stabilizes and supports cBAF function and cooperates in promoting TE-cell fate trajectories. The effects of cBAF manipulation on antitumor therapies were also evaluated. CD8+ T cells depleted of SMARCD2 (a BAF component) or ARID1A showed improved tumor control in murine cancer models. Treatment with BRD-K98645985, an inhibitor of ARID1A-containing BAF complexes, during initial CD8+ T-cell activation prior to chimeric antigen receptor (CAR) T-cell generation improved antitumor immunity by the CAR-T cells. Similar results were also shown in a model of human activated CD8+ T cells. In conclusion, this study provides insight into mechanisms that underlie activated T-cell fate and suggests harnessing this understanding to improve antitumor immunity.

Guo A, Huang H, Zhu Z, Chen MJ, Shi H, Yuan S, et al. cBAF complex components and MYC cooperate early in CD8+ T cell fate. Nature 2022 Jun 22 [Epub ahead of print].

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