cBAF 复合物组分与 MYC 在 CD8+ T 细胞命运早期协同作用

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 MYC 8 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.