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

Abstract

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 vivo⁵, 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.