TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8 + T cell exhaustion
Open accessAbstract
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-1 high TIM3 high (“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.
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T cell exhaustion limits the efficacy of chimeric antigen receptor (CAR) T cell therapy against solid tumours.
“T cell exhaustion also limits the efficacy of chimeric antigen receptor (CAR) T cell therapy against solid tumours14–17.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [16]
NFAT-induced transcription factors, including NR4A and TOX, drive T cell exhaustion/dysfunction.
“NFAT-induced transcription factors, including NR4A and TOX, drive T cell exhaustion/dysfunction44–47.”
From Tumor-specific cholinergic CD4+ T lymphocytes guide immunosurveillance of hepatocellular carcinoma (2023) · cites this paper as [46]
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“Recent studies have identified TOX, TOX2, and AP-1 family members as central regulators of human T cell exhaustion that promote widespread transcriptional and epigenetic dysregulation (Alfei et al., 2019; Khan et al., 2019; Scott et al., 2019; Seo et al., 2019; Wang et al., 2019; Yao et al., 2019).”
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- Authors
- Seo, H., Chen, J., González-Avalos, E., Samaniego-Castruita, D., Das, A., Wang, Y. H., López-Moyado, I. F., Georges, R. O., Zhang, W., Onodera, A., Wu, C.-J., Lu, L.-F., Hogan, P. G., Bhandoola, A., & Rao, A.
- Affiliations
- La Jolla Institute for Immunology (US)
- Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037;
- National Institutes of Health (US)
- University of California San Diego (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-05-31
- Volume
- 116
- Issue
- 25
- Pages
- 12410-12415
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6589758
- OpenAlex
- W2947617159
- Cited by
- 808
- References
- 28
- Citations by year
- 2026: 135 · 2025: 115 · 2024: 104 · 2023: 128 · 2022: 100 · 2021: 109 · 2020: 95 · 2019: 22
- FWCI
- 32.50
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-09-16)
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- HHS | National Institutes of Health (AI109842, AI040127, AI108651, AI140095, GM007752)
- American Association for Cancer Research (18-40-18-SEO)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- TOX, TOX2, NR4A, CD8+ T cell exhaustion, chimeric antigen receptor T cells, tumor-infiltrating lymphocytes, NFAT, calcineurin, transcriptional regulatory networks, PD-1, TIM-3, inhibitory receptors, NF-κB, bZIP transcription factors, cancer immunotherapy, solid tumors
- MeSH terms
- Animals, Immunotherapy, Lymphocyte Depletion, Mice, Inbred C57BL, Neoplasms, Protein Binding, RNA, Messenger, Transcription Factors, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Mice, Tumor Microenvironment
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