生物
细胞毒性T细胞
CD8型
细胞生物学
癌症免疫疗法
免疫疗法
细胞命运测定
T细胞
癌症研究
免疫学
抗原
免疫系统
体外
遗传学
转录因子
基因
作者
Ao Guo,Hongling Huang,Zhexin Zhu,Jinan Chen,Hao Shi,Sujing Yuan,Piyush Sharma,Jon P. Connelly,Swantje Liedmann,Yogesh Dhungana,Zhenrui Li,Dalia Haydar,Mei Yang,Helen M. Beere,Jason T. Yustein,Christopher DeRenzo,Shondra M. Pruett-Miller,Jeremy Chase Crawford,Giedre Krenciute,Charles W.M. Roberts,Hongbo Chi,Douglas R. Green
出处
期刊:Nature
[Springer Nature]
日期:2022-06-22
卷期号:607 (7917): 135-141
被引量:48
标识
DOI:10.1038/s41586-022-04849-0
摘要
The identification of mechanisms to promote memory T (Tmem) cells has important implications for vaccination and anti-cancer immunotherapy1–4. Using a CRISPR-based screen for negative regulators of Tmem 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 (Teff) cells, and their loss promotes Tmem 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 Teff cells, whereas those with low MYC and low cBAF preferentially differentiate towards Tmem 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 Tmem cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy. cBAF is a negative determinant of memory T cell fate and the manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.
科研通智能强力驱动
Strongly Powered by AbleSci AI