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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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“Solid tumours are known to be associated with T cell dysfunction [33] and this trial will help explore if HD CAR-T cells can produce better responses.”
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BackgroundThe Complex Integration of T-cell Metabolism and Immunotherapy
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“Furthermore, Treg cells expressing TIM‐3 produce high amount of immunosuppressive IL‐10.214 All these features establish the multifaceted roles of TIM‐3 in contributing to a strong immunosuppressive TME.”
BackgroundInfluentialThe current state and future of T-cell exhaustion research
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“Indeed, it has been described that CD8 T cells infiltrating solid tumors exist in two dysfunctional states, either reversible or permanent, depending on the respective chromatin arrangements (41).”
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“However, a majority of patients lack durable response to immunotherapy such as immune checkpoint blockade, which is explained at least in part by the stable dysfunctional state of T cells shaped epigenetically [37, 38].”
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“These highly exhausted cells could be CD38 CD101 cells.(73) By the same token, PD-L1 cancer cells may make T cells too exhausted to be effectively treated with PD-L1 blockade.”
BackgroundSpatially mapping the immune landscape of melanoma using imaging mass cytometry
Moldoveanu, D., Ramsay, L., Lajoie, M., Anderson-Trocmé, L., Lingrand, M., Berry, D., Perus, L. J. M., Wei, Y., Moraes, C., Alkallas, R., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abi5072 · Cited by 125
Vascular Microenvironment, Tumor Immunity and Immunotherapy
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Connections Between Metabolism and Epigenetics in Programming Cellular Differentiation
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Potentiating adoptive cell therapy using synthetic IL-9 receptors
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Heterogeneity and fate choice: T cell exhaustion in cancer and chronic infections
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Self-citationA unified atlas of CD8 T cell dysfunctional states in cancer and infection
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Self-citationLesion-Level Response Dynamics to Programmed Cell Death Protein (PD-1) Blockade
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Overcoming cold tumors: a combination strategy of immune checkpoint inhibitors
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In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue
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DIALOGUE maps multicellular programs in tissue from single-cell or spatial transcriptomics data
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T-cell exhaustion in immune-mediated inflammatory diseases: New implications for immunotherapy
Gao, Z., Feng, Y., Xu, J., & Liang, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.977394 · Cited by 118
“Frontiers in Immunology 02 lived effector T-cells and memory precursor effector T-cells, which produce cytokines and chemokines and acquire the ability to kill target cells (6, 8).”
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Nutrient-driven histone code determines exhausted CD8 + T cell fates
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“…retain an imprint of exhaustion, which includes epigenetically permissive states for inhibitory receptors that ultimately impact on the cell’s recall potential (Youngblood et al., 2011; Utzschneider et al., 2016; Pauken et al., 2016; Philip et al., 2017; Schietinger et al., 2012; Ahn et al., 2016).”
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“In addition, different epigenetic T-cell states influence the reprogrammability and dysfunction of exhausted PD-1+ T-cells [127].”
BackgroundTissue-resident memory CD8 T cell diversity is spatiotemporally imprinted
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LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade
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Chromatin remodellers as therapeutic targets
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HMMRATAC: a Hidden Markov ModeleR for ATAC-seq
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“seq data we described before, MACS2 has been used to analyze ATAC-seq data in many 554 published works (23,44-48), and MACS2 and F-Seq is part of the ENCODE analysis pipeline for 555”
MethodRole of Methylation in Pro- and Anti-Cancer Immunity
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Memory T-Cell Heterogeneity and TerminologyPreprint
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Tumor-infiltrating CD8+ T cell antitumor efficacy and exhaustion: molecular insights
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“Importantly, blockade of these coinhibitory molecules reprograms T cell functions in several cancers [55].”
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Cellular and molecular mechanisms of CD8(+) T cell differentiation, dysfunction and exhaustion
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“Repeated TCR stimulation is essential [145,146] in promoting the continuous and progressive accumulation of histone trimethylation from an early stage in chronic LCMV or on tumour exposure, as exhaustion specific methylation patterns are evident in early TPEX and inherited by their TEX progeny [43,53,57,58,145].”
BackgroundSLAMF7 Signaling Reprograms T Cells toward Exhaustion in the Tumor Microenvironment
O’Connell, P., Hyslop, S., Blake, M. K., Godbehere, S., Amalfitano, A., & Aldhamen, Y. A. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.2000300 · Cited by 97
Mechanisms of CAR T cell exhaustion and current counteraction strategies
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“Besides, the exhausted T cells had distinct transcriptional, epigenetic, and metabolic signatures (Doering et al., 2012; Schietinger and Greenberg, 2014; Philip et al., 2017).”
Background
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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