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

Xingying Zhang, Chenze Zhang, Miaomiao Qiao, Chen Cheng, Na Tang, Shan Lu, Wen Sun, Beilei Xu, Yuanwei Cao, Xiaofei Wei, Yao Wang, Weidong Han, Haoyi Wang

Cancer cell 2022 Nov 14

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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. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Xingying Zhang, Chenze Zhang, Miaomiao Qiao, Chen Cheng, Na Tang, Shan Lu, Wen Sun, Beilei Xu, Yuanwei Cao, Xiaofei Wei, Yao Wang, Weidong Han, Haoyi Wang. Depletion of BATF in CAR-T cells enhances antitumor activity by inducing resistance against exhaustion and formation of central memory cells. Cancer cell. 2022 Nov 14;40(11):1407-1422.e7