生物
癌症研究
效应器
转录因子
细胞生长
细胞
嵌合抗原受体
细胞生物学
T细胞
免疫学
基因
遗传学
免疫系统
作者
Xingying Zhang,Chenze Zhang,Miaomiao Qiao,Chen Cheng,Na Tang,Shan Lu,Wen Sun,Beilei Xu,Yuchen Cao,Xiaofei Wei,Yao Wang,Weidong Han,Haoyi Wang
出处
期刊:Cancer Cell
[Elsevier]
日期:2022-11-01
卷期号:40 (11): 1407-1422.e7
被引量:34
标识
DOI:10.1016/j.ccell.2022.09.013
摘要
Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors, and one major challenge is T cell exhaustion. To address this challenge, we performed a candidate gene screen using a hypofunction CAR-T cell model and found that depletion of basic leucine zipper ATF-like transcription factor (BATF) improved the antitumor performance of CAR-T cells. In different types of CAR-T cells and mouse OT-1 cells, loss of BATF endows T cells with improved resistance to exhaustion and superior tumor eradication efficacy. Mechanistically, we found that BATF binds to and up-regulates a subset of exhaustion-related genes in human CAR-T cells. BATF regulates the expression of genes involved in development of effector and memory T cells, and knocking out BATF shifts the population toward a more central memory subset. We demonstrate that BATF is a key factor limiting CAR-T cell function and that its depletion enhances the antitumor activity of CAR-T cells against solid tumors.
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