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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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“In addition, since terminally exhausted CD8 T cells undergo epigenetic changes that prevents for this phenotype to be rescued (49, 50), finding the appropriate therapeutic window before HBV-specific T cells become”
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“During chronic viral infection, epigenetic reprogramming leads to cytotoxic T cells exhaustion limiting T cells’ ability to recognize and kill non-self and infected cells (26).”
BackgroundPirozyan, M. R., McGuire, H. M., Emran, A. A., Tseng, H.-Y., Tiffen, J. C., Lee, J. H., Carlino, M. S., Menzies, A. M., Long, G. V., Scolyer, R. A., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00372 · Cited by 34
“Exhausted T cells appear to exist in 2 forms; one that is reversible by anti-PD-1 (22) and one that cannot be reversed and is believed to result frommore prolonged antigen exposure (23).”
BackgroundLeung, E. L., Li, R.-Z., Fan, X., Wang, L. Y., Wang, Y., Jiang, Z., Huang, J., Pan, H., Fan, Y., Xu, H., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40631-0 · Cited by 36
“It has been reported that the irreversible TIM3 and CD101 expression is an hallmark of CD8 + T cells exhaustion during infection 16,17 , which is consistent with our results.”
Engel, N. W., Steinfeld, I., Ryan, D., Anupindi, K., Kim, S., Wellhausen, N., Chen, L., Wilkins, K., Baker, D. J., Rommel, P. C., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2427216122 · Cited by 39
Epigenetic Regulation Of Axon Regeneration and Glial Activation in Injury Responses
Wahane, S., Halawani, D., Zhou, X., & Zou, H. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00640 · Cited by 36
The development of CD8 T-cell exhaustion heterogeneity and the therapeutic potentials in cancer
Zhang, J., Lei, F., & Tan, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1166128 · Cited by 39
“However, during persistent infection and tumorigenesis, the Tex represent a distinct T-cell lineage (9, 19, 20).”
BackgroundCheng, J., Xiao, Y., Peng, T., Zhang, Z., Qin, Y., Wang, Y., Shi, J., Yan, J., Zhao, Z., He, Z., et al. (2025) · Nature Cancer · doi:10.1038/s43018-024-00892-0 · Cited by 37
“To test this hypothesis, we first examined the chromatin accessibility of ETV7 in tumor-infiltrating CD8 + T cells from basal cell carcinoma 21 and melanoma 27 .”
Qin, Y., Huo, F., Feng, Z., Hou, J., Ding, Y., Wang, Q., Gui, Y., Yang, Z., Yang, J., Zhou, G., et al. (2025) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.0948 · Cited by 35
Hope, J. L., Stairiker, C. J., Bae, E., Otero, D. C., & Bradley, L. M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01595 · Cited by 38
“Those cells within the fixed dysfunctional chromatin state are resistant to reprogramming and express high levels of CD38 and CD101, whereas PD-1 TIL lacking CD38 and CD101 can undergo reprogramming to develop into effector cells (160).”
BackgroundA cellular census of human peripheral immune cells identifies novel cell states in lung diseases
Song, D., Yan, F., Fu, H., Li, L., Hao, J., Zhu, Z., Ye, L., Zhang, Y., Jin, M., Dai, L., et al. (2021) · Clinical and Translational Medicine · doi:10.1002/ctm2.579 · Cited by 35
Wong, W., Yin, B., Lam, C. Y. K., Huang, Y., Yan, J., Tan, Z., & Wong, S. H. D. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.783227 · Cited by 35
“Two distinct T cell dysfunctionassociated chromatin accessibility states were identified: (1) dysfunctional plastic state and (2) fixed dysfunctional state (Philip et al., 2017).”
BackgroundMinnie, S. A., Waltner, O. G., Ensbey, K. S., Nemychenkov, N. S., Schmidt, C. R., Bhise, S. S., Legg, S. R. W., Campoy, G., Samson, L. D., Kuns, R. D., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abo3420 · Cited by 36
Wells, A. C., Hioki, K. A., Angelou, C. C., Lynch, A. C., Liang, X., Ryan, D. J., Thesmar, I., Zhanybekova, S., Žuklys, S., Ullom, J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40959-7 · Cited by 35
Rational administration sequencing of immunochemotherapy elicits powerful anti-tumor effect
Zhu, C., Shi, Y., Li, Q., Luo, L., Li, X., Luo, Z., Lu, Y., Zhang, J., Jiang, M., Qin, B., et al. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.12.022 · Cited by 34
Barnkob, M. B., Michaels, Y. S., André, V., Macklin, P. S., Gileadi, U., Valvo, S., Rei, M., Kulicke, C. A., Chen, J., Jain, V., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47424-z · Cited by 34
Immune Cell Migration to Cancer
Ryan, A. T., Kim, M., & Lim, K. (2024) · Cells · doi:10.3390/cells13100844 · Cited by 35
SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery
Hu‐Lieskovan, S., Bhaumik, S., Dhodapkar, K. M., Grivel, J., Gupta, S. V., Hanks, B. A., Janetzki, S., Kleen, T. O., Koguchi, Y., Lund, A. W., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000705 · Cited by 35
Active surveillance characterizes human intratumoral T cell exhaustion
You, R., Artichoker, J., Fries, A. C., Edwards, A. W., Combes, A. J., Reeder, G. C., Samad, B., & Krummel, M. F. (2021) · Journal of Clinical Investigation · doi:10.1172/jci144353 · Cited by 35
Targeting the epigenetic processes to enhance antitumor immunity in small cell lung cancer
Luo, H., Shan, J., Zhang, H., Song, G., Li, Q., & Xu, C. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.02.018 · Cited by 34
Medikonda, R. T., Abikenari, M. A., Schonfeld, E., & Lim, M. K. (2025) · Cancers · doi:10.3390/cancers17111881 · Cited by 35
“Exhausted TILs in GBM have a unique TOX-regulated transcriptional signature that includes NR4A, EOMES, and BATF, which exert chromatin modulation and suppress effector gene loci [116].”
Nelson, C. E., Thompson, E. A., Quarnstrom, C. F., Fraser, K. A., Seelig, D. M., Bhela, S., Burbach, B. J., Masopust, D., & Vezys, V. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.038 · Cited by 31
“These data mirror the dysfunction of tumor-specific CD8 T cells, which is thought to be fixed by day 14 after initial antigen encounter (Philip et al., 2017; Schietinger et al., 2012., 2016).”
ResultQiu, R., Yu, X., Wang, L., Han, Z., Yao, C., Cui, Y., Hou, G., Dai, D., Jin, W., & Shen, N. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.2000060 · Cited by 36
“It was successfully used to study chromatin dynamics of regulatory T cells under inflammatory condition (24), development of plasmacytoid dendritic cells (25), and tumor-specific CD8 T cells (26).”
MethodBrennick, C. A., George, M. M., Moussa, M. M., Hagymasi, A. T., Seesi, S. A., Shcheglova, T. V., Englander, R. P., Keller, G. L. J., Balsbaugh, J. L., Baker, B. M., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci142823 · Cited by 31
“The MFI of Tcf1 expression by the TILs of the 3 groups was consistent with this interpretation.”
InfluentialSelf-citationAnti-CAIX BBζ CAR4/8 T cells exhibit superior efficacy in a ccRCC mouse model
Wang, Y., Buck, A., Grimaud, M., Culhane, A. C., Kodangattil, S. R., Razimbaud, C., Bonal, D. M., Nguyen, Q., Zhu, Z., Wei, K. S., et al. (2021) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2021.12.019 · Cited by 34
“We did observe the induction of strong intrinsic activation of the type I IFN pathway in 28BBz CAR-T cells (cluster 13) as reported before(14) as well as cluster 14, which has upregulated CD38 TIGIT expression (Figure S5).(46) 28z had significantly more CD8 Treg cells, while 28BBz and BBz had few CD8 Treg cells (Figur…”
BackgroundJiang, L., Dai, S., Li, J., Liang, X., Qu, L., Chen, X., Guo, M., Chen, Z., Chen, L., Wei, H., et al. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010730 · Cited by 32
“NR4A receptors are expressed at high levels in CD8+ T cells from humans with cancer or chronic viral infections and are linked to the induction of T cell dysfunction (10-12).”
BackgroundApplications of Single-Cell Omics to Dissect Tumor Microenvironment
Guo, T., Li, W., & Cai, X. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.548719 · Cited by 33
Arming a killer: mitochondrial regulation of CD8+ T cell cytotoxicity
Lisci, M., & Griffiths, G. M. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.05.007 · Cited by 29
Riegel, D., Romero-Fernández, E., Simon, M., Adenugba, A., Singer, K., Mayr, R., Weber, F., Kleemann, M., Imbusch, C. D., Kreutz, M. P., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2022.12.029 · Cited by 35
DeRogatis, J. M., Neubert, E. N., Viramontes, K. M., Henriquez, M. L., Nicholas, D., & Tinoco, R. (2023) · Journal of Virology · doi:10.1128/jvi.00225-23 · Cited by 30
“possible inhibitor of T cell function (11, 22, 28).”
BackgroundOnyshchenko, K., Luo, R., Guffart, E., Gaedicke, S., Grosu, A., Firat, E., & Niedermann, G. (2023) · Nature Communications · doi:10.1038/s41467-023-37825-x · Cited by 31
“While we found the strongest expansion of triple treatment-induced tumor-speci fi c T cells in blood, we also observed substantial expansion of the CD101-negative subset of PD1 + TIM3 + TILs, i.e., of transitory cells which are non-terminally differentiated (effector-like) exhausted cells 5,51 .”
Qiu, F., Jiang, P., Zhang, G., An, J., Ruan, K., Lyu, X., Zhou, J., & Sheng, W. (2024) · Nature Communications · doi:10.1038/s41467-024-48607-4 · Cited by 35
Epigenetic regulation of T cell exhaustion in cancer
Kang, T. G., Johnson, J. T., Zebley, C. C., & Youngblood, B. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00883-y · Cited by 36
Watanabe, T., Gaedicke, S., Guffart, E., Firat, E., & Niedermann, G. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0476 · Cited by 30
Exploiting the obesity-associated immune microenvironment for cancer therapeutics
Desharnais, L., Walsh, L. A., & Quail, D. F. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107923 · Cited by 31
Galva, L. D. C., Jiang, X., Hussein, M. S., Zhang, H., Mao, R., Brody, P. A., Chi, X., Peng, Y., He, A. R., Kehinde‐Ige, M., et al. (2021) · Hepatology · doi:10.1002/hep.32279 · Cited by 31
“Recent study showed that the effector function of this PDlo, but not PDhi T cells, was reversible by checkpoint blockade.[48] These functionreversible lightly exhausted (PD1lo) lowavidity CARTs will create an opportunity for combination therapy.”
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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