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 1529-2908

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.

Item Type:	Article
Keywords:	CAR T cells, BATF, IRF4, exhaustion
Date Deposited:	31 Jul 2021 00:45
Last Modified:	31 Jul 2021 00:45
URI:	https://oak.novartis.com/id/eprint/45392