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Chromatin states define tumour-specific T cell dysfunction and reprogramming
Open accessAbstract
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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“Additionally, comparison of liver-resident effector Tag+ T cells generated from an acute Listeria monocytogenes infection with exhausted Tag+ T cells generated in AST-CRE-ERT2 mice (liver tumor) (27) indicated that both transporters Slco3a1 and Abcb1a were significantly down-regulated in exhausted CD8+ T cells relative to the effector cells (fig. S8B).”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [27]
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“It is also possible that combination therapy may be sufficient to reverse T cell exhaustion, although this is unlikely, given the kinetics of these experiments and recent evidence that epigenetic programs enforce an exhausted cell state (29, 30).”
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BackgroundModulating Glycolysis to Improve Cancer Therapy
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Metadata
- 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
- Venue
- Nature
- Published
- 2017-05
- Volume
- 545
- Issue
- 7655
- Pages
- 452-456
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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