cBAF complex components and MYC cooperate early in CD8⁺ T cell fate

The identification of mechanisms to promote memory T (T-mem) cells has important implications for vaccination and anti-cancer immunotherapy(1-4). Using a CRISPR-based screen for negative regulators of T(mem )cell generation in vivo(5), here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF)(6,7). Several components of the cBAF complex are essential for the differentiation of activated CD8+ T cells into T effector (T-eff) cells, and their loss promotes T-mem cell formation in vivo. During the first division of activated CD8(+) T cells, cBAF and MYC8 frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high MYC and high cBAF display a cell fate trajectory towards T-eff cells, whereas those with low MYC and low cBAF preferentially differentiate towards T-mem cells. The cBAF complex and MYC physically interact to establish the chromatin landscape in activated CD8(+) T cells. Treatment of naive CD8(+) T cells with a putative cBAF inhibitor during the first 48 h of activation, before the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves efficacy in a mouse solid tumour model. Our results establish cBAF as a negative determinant of T-mem cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.