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

The identification of mechanisms to promote memory T (T) cells has important implications for vaccination and anti-cancer immunotherapy. Using a CRISPR-based screen for negative regulators of T cell generation in vivo, here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF). Several components of the cBAF complex are essential for the differentiation of activated CD8 T cells into T effector (T) cells, and their loss promotes T cell formation in vivo. During the first division of activated CD8 T cells, cBAF and MYC frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high MYC and high cBAF display a cell fate trajectory towards T cells, whereas those with low MYC and low cBAF preferentially differentiate towards T 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 cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.