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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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“43,46,47 We detected no difference in T-bet expression in CD8 + or CD4 + cells after NET inhibition (Figure 4E).”
New insights into progenitor exhausted T cell populations
Ahmed, R., Hofmann, M., Kallies, A., Oxenius, A., Philip, M., Wherry, E. J., Ye, L., & Zehn, D. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-026-01328-9 · Cited by 7
“TCF1 expression does not in and of itself confer increased effector function to CD8 + T cells, and TCF1-expressing tumour-specific T cells can be completely dysfunctional 20,21 .”
Self-citationZhu, A., Ren, H., Li, X., Yang, W., Han, X., Hou, X., Zhang, S., Li, S., Xie, Y., Yu, M., et al. (2024) · Nano Today · doi:10.1016/j.nantod.2024.102590 · Cited by 5
Impact of multiple hits with cognate antigen on memory CD8+ T-cell fate
Takamura, S. (2020) · International Immunology · doi:10.1093/intimm/dxaa039 · Cited by 5
Effector and cytolytic function of natural killer cells in anticancer immunity
Karmakar, S., Mishra, A., Pal, P., & Lal, G. (2023) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiad126 · Cited by 5
Kakimi, K., & Sugie, T. (2025) · Breast Cancer · doi:10.1007/s12282-025-01707-5 · Cited by 7
“ATAC-seq analysis demonstrated that the epigenetic profile of exhausted T cells remains largely unchanged following PD-1 blockade, resulting in only partial restoration of function [34].”
Belizário, J. E., & Rodrigues, M. F. S. D. (2020) · Therapeutic Advances in Vaccines and Immunotherapy · doi:10.1177/2515135520904238 · Cited by 6
NKG2D defines tumor‐reacting effector CD8+ T cells within tumor microenvironment
Mojić, M., Shitaoka, K., Ohshima, C., Ucche, S., Lyu, F., Hamana, H., Tahara, H., Kishi, H., & Hayakawa, Y. (2021) · Cancer Science · doi:10.1111/cas.15050 · Cited by 5
Novel targets for immunotherapy associated with exhausted CD8 + T cells in cancer
Zhang, L., Zhang, B., Li, L., Ye, Y., Wu, Y., Yuan, Q., Xu, W., Wen, X., Guo, X., & Nian, S. (2022) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-022-04326-1 · Cited by 6
Bacteriolytic therapy with Clostridium ghonii for experimental solid tumors
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The Development, Function, and Plasticity of the Immune Macroenvironment in CancerPreprint
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“However, recent studies have demonstrated that cytotoxic T cells within the TME are highly and irreversibly dysfunctional, acquiring epigenetic programs that render them incapable of normal effector functions, such as proliferation, cytokine production, and cytolysis 5 .”
BackgroundTCF-1 regulates NKG2D expression on CD8 T cells during anti-tumor responsesPreprint
Harris, R., Mammadli, M., Hiner, S., Suo, L., Yang, Q., Sen, J. M., & Karimi, M. A. (2022) · Research Square · doi:10.21203/rs.3.rs-1910637/v1 · Cited by 5
NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustionPreprint
Dahabieh, M. S., DeCamp, L. M., Oswald, B. M., Kitchen-Goosen, S. M., Fu, Z. F., Vos, M., Compton, S. E., Longo, J., Williams, K. S., Ellis, A. E., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.23.600279 · Cited by 5
Vaccination generates functional progenitor tumor-specific CD8 T cells and long-term tumor control
Román, C. R. D., Erwin, M. M., Rudloff, M. W., Revetta, F. L., Murray, K. A., Favret, N. R., Roetman, J. J., Roland, J. T., Washington, M. K., & Philip, M. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009129 · Cited by 4
“19 21–25 While nearly all TCR TAG in mice with late lesions were dysfunctional and failed to produce effector cytokines, mice with early lesions retained a subset of IFN γ -producing TCR TAG , even at 21 days (figure 3D).”
InfluentialSelf-citationBispecific antibody combination therapies in diffuse large B‐cell lymphoma
Harrop, S., Minson, A. G., Steiner, T. M., Neeson, P. J., & Dickinson, M. J. (2025) · British Journal of Haematology · doi:10.1111/bjh.70228 · Cited by 4
“27,28 T-cell exhaustion that is either pre-existing or acquired is thought to be a common mechanism of resistance to T-cell redirecting therapies.”
Miltefosine reinvigorates exhausted T cells by targeting their bioenergetic state
Zhang, X., Zhang, C., Lu, S., Dong, J., Tang, N., Wang, Y., Han, W., Pan, X., Zhang, X., Liu, D., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101869 · Cited by 4
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The Heightened Importance of EZH2 in Cancer Immunotherapy
Lin, X., Zhou, W., Lin, C., & Cao, W. (2023) · Cancer Screening and Prevention · doi:10.14218/csp.2023.00006 · Cited by 6
Xia, R.-J., Du, X., Shen, L.-W., Ma, J., Xu, S., Fan, R.-F., Qin, J.-W., & Yan, L. (2024) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v16.i9.3820 · Cited by 5
“Initially, the dysfunction of TSTs is reversible but ultimately becomes irreversible, even when dysfunctional T cells are removed from the TME and undergo multiple rounds of cell division[10].”
T Cell Exhaustion in Allergic Diseases and Allergen Immunotherapy: A Novel Biomarker?
Xu, Q., Li, L., & Zhu, R. (2025) · Current Allergy and Asthma Reports · doi:10.1007/s11882-025-01199-5 · Cited by 7
“Furthermore, T cell exhaustion is linked to chromatin changes, with two distinct states identified: a plastic dysfunctional state amenable to reinvigora-tion and a fixed dysfunctional state resistant to remodeling [32, 33].”
Wang, P., Wang, Y., Jiang, Y., Li, M., Li, G., & Qiao, Q. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.564306 · Cited by 4
“Anti-PD1 treatment could revive early-stage dysfunctional T cells but not late-stage dysfunctional T cells (34), which supported our results.”
ResultA Review of Proteomics Strategies to Study T-Cell Activation and Function in Cancer Disease
Papale, M. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1507-2_9 · Cited by 4
Li, D.-H., & Xiong, X. (2024) · Clinical Cosmetic and Investigational Dermatology · doi:10.2147/ccid.s451386 · Cited by 5
Saman, H. T., Saman, H. T., Shahab Uddin, M. S., Raza, S. S., Shrimali, R. K., & Rasul, K. I. (2020) · Clinical Oncology and Research · doi:10.31487/j.cor.2020.09.08 · Cited by 3
“showed that at early stages the TEX state is reversible and provide a window of opportunity to PD-1 inhibition to work, however, a more prolonged exposure to tumor specific antigens causes irreversible epigenetic dysfunction that renders chromatin unreachable and impervious to more reconditioning and revival [84].”
BackgroundPerspectives on Epigenetics and Cancer Immunotherapy: A Preface to Special Issue
Álvarez‐Errico, D. (2021) · Cancers · doi:10.3390/cancers13061452 · Cited by 5
“Extensive epigenetic reprogramming of immune cells in response to an immunosuppressive TME underlies pro-tumorigenic mechanisms such as T cell exhaustion [2], the polarization of macrophages to an anti-inflammatory phenotype [3], or differentiation into myeloid-derived suppressor cells (MDSCs) [4].”
BackgroundUFL1 promotes survival and function of virtual memory CD8 T cells
Bhatt, B., Kumar, K., Shi, H., Ganesan, D., Anazodo, F. I., Rathakrishnan, A., Zhu, H., Wanna, A., Jiang, C., Jayavelu, T., et al. (2025) · The Journal of Immunology · doi:10.1093/jimmun/vkae042 · Cited by 3
Chiello, J. L., Shaikh, N., Jacobi, J. J., Gaulin, N., Santos, G. S., Keck, C., Hess, S. M., Lichty, B. D., Singh, P. K., Rosario, S. R., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.09.047 · Cited by 4
Advancing adoptive T cell therapy in ovarian cancer: barriers, innovations, and emerging platforms
Santos, G. N. D. S., DeJohn, C. R., Hess, S. M., Zsíros, E., & McGray, A. R. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-013285 · Cited by 3
T Cell Exhaustion in Hepatocellular Carcinoma: A Substantial Barrier in Immunotherapy
Nouri, K., Aasadollahei, N., Haghir-Sharif-Zamini, Y., Seydi, H., Salehi, M., Mesdaghi, M., Najimi, M., & Vosough, M. (2026) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.71044 · Cited by 5
“Two PD-1 hi subsets were identified: early-stage T EX cells (day 5, CD38 lo /CD101 lo ), which respond to IL-15, and late-stage T EX cells (post-day 12, CD38 hi /CD101 hi ), which fail to recover due to fixed chromatin landscapes, as shown by ATAC-seq [42].”
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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