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Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12410-12415. doi: 10.1073/pnas.1905675116. Epub 2019 May 31.

TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion.

Author information

1
Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037.
2
Biomedical Sciences Graduate Program, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
3
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
4
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
5
Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093.
6
Biological Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093.
7
National Cancer Institute, National Institutes of Health, Bethesda, MD 20184.
8
Bioengineering Graduate Program, Bioengineering Department, University of California, San Diego, La Jolla, CA 92093.
9
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
10
Institute for Global Prominent Research, Chiba University, Chiba 263-8522, Japan.
11
Division of Biological Sciences, Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093.
12
Program in Immunology, University of California, San Diego, La Jolla, CA 92037.
13
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
14
Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037; arao@lji.org.

Abstract

T cells expressing chimeric antigen receptors (CAR T cells) have shown impressive therapeutic efficacy against leukemias and lymphomas. However, they have not been as effective against solid tumors because they become hyporesponsive ("exhausted" or "dysfunctional") within the tumor microenvironment, with decreased cytokine production and increased expression of several inhibitory surface receptors. Here we define a transcriptional network that mediates CD8+ T cell exhaustion. We show that the high-mobility group (HMG)-box transcription factors TOX and TOX2, as well as members of the NR4A family of nuclear receptors, are targets of the calcium/calcineurin-regulated transcription factor NFAT, even in the absence of its partner AP-1 (FOS-JUN). Using a previously established CAR T cell model, we show that TOX and TOX2 are highly induced in CD8+ CAR+ PD-1high TIM3high ("exhausted") tumor-infiltrating lymphocytes (CAR TILs), and CAR TILs deficient in both TOX and TOX2 (Tox DKO) are more effective than wild-type (WT), TOX-deficient, or TOX2-deficient CAR TILs in suppressing tumor growth and prolonging survival of tumor-bearing mice. Like NR4A-deficient CAR TILs, Tox DKO CAR TILs show increased cytokine expression, decreased expression of inhibitory receptors, and increased accessibility of regions enriched for motifs that bind activation-associated nuclear factor κB (NFκB) and basic region-leucine zipper (bZIP) transcription factors. These data indicate that Tox and Nr4a transcription factors are critical for the transcriptional program of CD8+ T cell exhaustion downstream of NFAT. We provide evidence for positive regulation of NR4A by TOX and of TOX by NR4A, and suggest that disruption of TOX and NR4A expression or activity could be promising strategies for cancer immunotherapy.

KEYWORDS:

CD8+ T cell hyporesponsiveness; NFAT; NR4A; TOX; TOX2

PMID:
31152140
PMCID:
PMC6589758
[Available on 2019-11-30]
DOI:
10.1073/pnas.1905675116

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