TOX is a critical regulator of tumour-specific T cell differentiation
Open accessAbstract
Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states 1-6. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.
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The CD8 T-cell population is diverse rather than uniform.
“CD8 T cells are typically regarded as a uniform population with cytotoxic function; however, recent studies have highlighted the diversity of the CD8 T-cell population (5)(6)(7)(8)(9).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [6]
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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).”
BackgroundResult
- Authors
- Scott, A. C., Dündar, F., Zumbo, P., Chandran, S. S., Klebanoff, C. A., Shakiba, M., Trivedi, P., Menocal, L., Appleby, H., Camara, S., Zamarin, D., Walther, T., Snyder, A., Femia, M. R., Comen, E. A., Wen, H. Y., Hellmann, M. D., Anandasabapathy, N., Liu, Y., Altorki, N. K., Lauer, P., Levy, O., Glickman, M. S., Kaye, J., Betel, D., Philip, M., & Schietinger, A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Weill Cornell Medicine (US)
- Cornell University (US)
- NewYork–Presbyterian Hospital (US)
- Aduro BioTech (United States) (US)
- Cedars-Sinai Medical Center (US)
- Corresponding author
- Philip, Mary
- Schietinger, Andrea
- ORCID
- Scott, Andrew C.
- Dündar, Friederike
- Zumbo, Paul
- Chandran, Smita S.
- Klebanoff, Christopher A.
- Shakiba, Mojdeh
- Menocal, Laura
- Zamarin, Dmitriy
- Snyder, Alexandra
- Femia, Matthew R.
- Comen, Elizabeth A.
- Wen, Hannah Y.
- Hellmann, Matthew D.
- Anandasabapathy, Niroshana
- Liu, Yong
- Altorki, Nasser K.
- Lauer, Peter
- Glickman, Michael S.
- Kaye, Jonathan
- Betel, Doron
- Philip, Mary
- Schietinger, Andrea
- Venue
- Nature
- Published
- 2019-06-17
- Volume
- 571
- Issue
- 7764
- Pages
- 270-274
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7698992
- OpenAlex
- W2951598503
- Cited by
- 1,106
- References
- 46
- Citations by year
- 2026: 132 · 2025: 143 · 2024: 150 · 2023: 175 · 2022: 151 · 2021: 193 · 2020: 131 · 2019: 26 · 2014: 1
- FWCI
- 50.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (R00CA172371, K08CA158069, U54CA209975, DP2CA225212, P30CA008748)
- National Institute of Allergy and Infectious Diseases (R01AI054977)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK058404)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR070234)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- TOX transcription factor, tumor-specific T cells, CD8+ T cell exhaustion, T cell differentiation, inhibitory receptors, chronic viral infection, NFAT activation, T cell receptor stimulation, TCF1, T cell dysfunction, tumor immunology, chromatin accessibility
- MeSH terms
- Animals, Cell Differentiation, High Mobility Group Proteins, Humans, Immunologic Memory, Neoplasms, Phenotype, Receptors, Antigen, T-Cell, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Lymphocytes, Tumor-Infiltrating, Homeodomain Proteins, CD8-Positive T-Lymphocytes, Epigenesis, Genetic, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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