As development of CD8+ T cell exhaustion is mediated by transcription factors (TFs), Seo et al. examined the effects of overexpression of BATF – one of the TFs that favors full T cell effector function – on exhaustion. In a mouse model, BATF transduction of CAR T cells resulted in: a) expansion of CAR TILs, b) lower percentage of TILS with exhaustion phenotype, c) enhanced tumor rejection, and d) generation of a memory response to tumor rechallenge. BATF-dependent enhancements were dependent upon interaction with the TF IRF4. Human CAR T cells transduced with BATF demonstrated enhanced tumor-specific proliferation and cytotoxicity in vitro.
Contributed by Margot O’Toole
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.
Author Info: (1) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. Novartis Institutes for BioMedical Research, Cambridge, MA, USA. (2) Division o
Author Info: (1) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. Novartis Institutes for BioMedical Research, Cambridge, MA, USA. (2) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, USA. (3) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. Bioengineering Graduate Program, Bioengineering Department, University of California, San Diego, La Jolla, CA, USA. (4) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. Contiguous BS/MS Program, Biology Department, University of California, San Diego, La Jolla, CA, USA. Novartis Institutes for BioMedical Research, Cambridge, MA, USA. (5) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. (6) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, USA. (7) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. arao@lji.org. Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA. arao@lji.org. Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA. arao@lji.org. Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. arao@lji.org. Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA, USA. arao@lji.org. (8) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. phogan@lji.org. Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. phogan@lji.org. Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA, USA. phogan@lji.org.
