Depletion of BATF in CAR-T cells enhances antitumor activity by inducing resistance against exhaustion and formation of central memory cells

• Published in: Cancer cell 2022-11, Vol.40 (11), p.1407-1422.e7
• Main Authors: Zhang, Xingying, Zhang, Chenze, Qiao, Miaomiao, Cheng, Chen, Tang, Na, Lu, Shan, Sun, Wen, Xu, Beilei, Cao, Yuanwei, Wei, Xiaofei, Wang, Yao, Han, Weidong, Wang, Haoyi
• Format: Article
• Language: English
• Subjects: Animals; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; BATF; CAR-T cell hypofunction model; gene editing; Gene Expression Regulation; Humans; immunotherapy; Immunotherapy, Adoptive; Mice; Neoplasms - genetics; Neoplasms - therapy; T cell exhaustion; Transcription Factors - genetics
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2022.09.013

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. [Display omitted] •Development of an in vitro CAR-T cell hypofunction model for genetic screen•BATF depletion enhances CAR-T cells efficacy against solid tumors•BATF drives CAR-T cell exhaustion by binding to and upregulating related genes•BATF editing induces formation of more central memory CAR-T cells Zhang et al. establish an in vitro CAR-T cell hypofunction model and identify that BATF drives T cell exhaustion and represses formation of a central memory subset by binding to and regulating related genes in CAR-T cells. Depletion of BATF enhances the antitumor activity of CAR-T cells against solid tumors.