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

Cited 127 time in Web of Science Cited 133 time in Scopus
Authors

Seo, Hyungseok; González-Avalos, Edahí; Zhang, Wade; Ramchandani, Payal; Yang, Chao; Lio, Chan-Wang J.; Rao, Anjana; Hogan, Patrick G.

Issue Date
2021-08
Publisher
Nature Publishing Group
Citation
Nature Immunology, Vol.22 No.8, pp.983-995
Abstract
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.
ISSN
1529-2908
URI
https://hdl.handle.net/10371/192600
DOI
https://doi.org/10.1038/s41590-021-00964-8
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