Abstract
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.
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