Cited by 934Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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Chromatin states define tumour-specific T cell dysfunction and reprogramming

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Philip, Mary, Fairchild, Lauren, Sun, Liping, Horste, Ellen L., Camara, Steven, Shakiba, Mojdeh, Scott, Andrew C., Viale, Agnes, Lauer, Peter, Merghoub, Taha, Hellmann, Matthew D., Wolchok, Jedd D., Leslie, Christina S., Schietinger, Andrea·2017·Nature

DOI 10.1038/nature22367PMC PMC5693219

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Abstract

Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1 hi dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1 hi tumour-infiltrating CD8 T cells. Our study has important implications for cancer immunotherapy as we define key transcription factors and epigenetic programs underlying T cell dysfunction and surface markers that predict therapeutic reprogrammability.

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Additional file 1 of Low muscle mass in lung cancer is associated with an inflammatory and immunosuppressive tumor microenvironment
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Additional file 2 of Low muscle mass in lung cancer is associated with an inflammatory and immunosuppressive tumor microenvironment
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Influential
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B cell-derived type I interferon sustains T cell functionality upon strong TCR stimulation during chronic infection
de Graça, C. G., Cao, Y., Li, S. F., Lindemann, A. F., Heyden, L., Wijesinghe, S. K. M., Poch, A., Nguyen, M.-H. T., Huynh-Anh, N. T., Daum, E., et al. (2026) · Immunity · doi:10.1016/j.immuni.2026.06.003

Authors: Philip, M., Fairchild, L., Sun, L., Horste, E. L., Camara, S., Shakiba, M., Scott, A. C., Viale, A., Lauer, P., Merghoub, T., Hellmann, M. D., Wolchok, J. D., Leslie, C. S., & Schietinger, A.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Aduro BioTech (United States) (US)
Corresponding author: Schietinger, Andrea
ORCID: Philip, Mary
Fairchild, Lauren
Sun, Liping
Shakiba, Mojdeh
Scott, Andrew C.
Viale, Agnes
Lauer, Peter
Merghoub, Taha
Hellmann, Matthew D.
Wolchok, Jedd D.
Leslie, Christina S.
Schietinger, Andrea
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2017-05
Volume: 545
Issue: 7655
Pages: 452-456
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature22367
PMC: PMC5693219
OpenAlex: W2616155686
Cited by: 933
References: 51
Citations by year: 2026: 92 · 2025: 104 · 2024: 104 · 2023: 111 · 2022: 113 · 2021: 126 · 2020: 123 · 2019: 90 · 2018: 58 · 2017: 12
FWCI: 34.11
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Human Genome Research Institute (U01HG007893)
National Cancer Institute (R00CA172371, K08CA158069, U54CA209975, P30CA008748)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: T cell dysfunction, chromatin state, epigenetic regulation, T cell exhaustion, PD-1, immune checkpoint blockade, T cell reprogramming, transcription factors, cell surface markers, solid tumors, cancer immunotherapy
MeSH terms: Animals, Chromatin, Female, Humans, Immunologic Memory, Male, Neoplasms, Transcription Factors, Gene Expression Regulation, Neoplastic, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Gene Expression Profiling, Epigenesis, Genetic, Mice

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Chromatin states define tumour-specific T cell dysfunction and reprogramming

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