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BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells.

Seo, Hyungseok, González-Avalos, Edahí, Zhang, Wade, Ramchandani, Payal, Yang, Chao, Lio, Chan-Wang J, Rao, Anjana and Hogan, Patrick G (2021) BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nature immunology. ISSN 1529-2916


The transcription factors nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1; Fos-Jun) cooperate to promote the effector functions of T cells, but NFAT in the absence of AP-1 imposes a negative feedback program of T cell hyporesponsiveness (exhaustion). Here, we show that basic leucine zipper ATF-like transcription factor (BATF) and interferon regulatory factor 4 (IRF4) cooperate to counter T cell exhaustion in mouse tumor models. Overexpression of BATF in CD8 T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumor-infiltrating CAR T cells, increased the production of effector cytokines, decreased the expression of inhibitory receptors and the exhaustion-associated transcription factor TOX and supported the generation of long-lived memory T cells that controlled tumor recurrence. These responses were dependent on BATF-IRF interaction, since cells expressing a BATF variant unable to interact with IRF4 did not survive in tumors and did not effectively delay tumor growth. BATF may improve the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.

Item Type: Article
Date Deposited: 03 Aug 2021 00:45
Last Modified: 03 Aug 2021 00:45


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