The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
BEDTools: a flexible suite of utilities for comparing genomic features
Quinlan, A. R., & Hall, I. M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq033 · Cited by 27,437
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386
Differential expression analysis for sequence count data
Anders, S., & Huber, W. (2010) · Genome Biology · doi:10.1186/gb-2010-11-10-r106 · Cited by 15,581
Robinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G., & Mesirov, J. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1754 · Cited by 15,390
MEME SUITE: tools for motif discovery and searching
Bailey, T. L., Boden, M., Buske, F. A., Frith, M., Grant, C. E., Clementi, L., Ren, J., Li, W. W., & Noble, W. S. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp335 · Cited by 10,648
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Rizvi, N. A., Hellmann, M. D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J. J., Lee, W., Yuan, J., Wong, P., Ho, T. S., et al. (2015) · Science · doi:10.1126/science.aaa1348 · Cited by 7,802
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Items 401–500 of 934
Gilbertson, S. E., Walter, H. C., Gardner, K., Wren, S. N., Vahedi, G., & Weinmann, A. S. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110769 · Cited by 31
Shi, X., Li, Z., Yao, R.-Q., Cheng, Q., Li, W., Wu, R. T., Xie, Z., Zhu, Y., Qiu, X., Yang, S., et al. (2022) · npj Precision Oncology · doi:10.1038/s41698-022-00300-9 · Cited by 31
The effector program of human CD8 T cells supports tissue remodeling
Delacher, M., Schmidleithner, L., Simon, M., Stüve, P., Sanderink, L., Hotz‐Wagenblatt, A., Wuttke, M., Schambeck, K., Ruhland, B., Hofmann, V., et al. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20230488 · Cited by 30
“…of several markers including PD1, TOX, and CD39, and a progressive reprogramming of the chromatin landscape, which leads to impaired effector molecule expression, proliferation, and survival (Alfei et al., 2019; Kallies et al., 2020; Khan et al., 2019; Philip et al., 2017; Scott et al., 2019).”
BackgroundBlise, K. E., Sivagnanam, S., Betts, C. B., Betre, K., Kirchberger, N. C., Tate, B. J., Furth, E. E., Costa, A. D., Nowak, J. A., Wolpin, B. M., et al. (2024) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-23-0873 · Cited by 31
Schnell, A., Schmidl, C., Herr, W., & Siska, P. J. (2018) · Biomedicines · doi:10.3390/biomedicines6010025 · Cited by 31
“As an example, first studies started to interrogate the chromatin accessibility landscape of TILs in mouse tumor models and/or primary melanoma samples [102,103], paving the way to connect chromatin signatures in T cells to immunotherapy treatment in the future.”
ResultThe epigenetic landscape of fate decisions in T cells
Jay, A., Pondevida, C. M., & Vahedi, G. (2025) · Nature Immunology · doi:10.1038/s41590-025-02113-x · Cited by 32
“…regions associated with naive CD8 + T cells after activation, major gain of de novo open chromatin regions in effector CD8 + T cells and similarity between CD8 + T M cells with both naive and effector CD8 + T cells in regards to open chromatin regions are consistently reported in mice 22,23,96,97 .”
PD-1 Blockade Unleashes Effector Potential of Both High- and Low-Affinity Tumor-Infiltrating T Cells
Martínez-Usatorre, A., Donda, A., Zehn, D., & Romero, P. J. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701644 · Cited by 29
Elia, A. R., Caputo, S., & Bellone, M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01786 · Cited by 30
“The latter cells are no longer reprogrammable by ICB (20).”
BackgroundPrognostic Values of CD38+CD101+PD1+CD8+ T Cells in Pancreatic Cancer
Zhang, M., Yang, J., Zhou, J., Gao, W., Zhang, Y., Lin, Y., Wang, H., Ruan, Z., & Ni, B. (2019) · Immunological Investigations · doi:10.1080/08820139.2019.1566356 · Cited by 29
“Recently, two research groups reported focused studies on the multiplicity of PD-1 expressing CD8+ TILs (Philip et al., 2017, Schietinger et al., 2016).”
BackgroundInfluentialEpigenetics of T cell fate decision
Pace, L., & Amigorena, S. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.01.002 · Cited by 30
Zhu, Y., Zhang, Z., Jiang, Z., Liu, Y., & Zhou, J. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.00369 · Cited by 29
Kong, X., Wei, G., Chen, N., Zhao, S., Shen, Y., Zhang, J., Li, Y., Zeng, X., & Wu, X. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008633 · Cited by 26
“According to our ATAC-seq data, consistent with data from the Drosophila melanogaster embryonic ATAC-seq profiles [23], BmN cells exhibited an expected nucleosomal insert size pattern (S1A Fig), which was different from the results in mammals [24].”
ResultQiu, J., Sharma, S., Rollins, R. A., & Paul, T. A. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0072 · Cited by 30
Indini, A., Fiorilla, I., Ponzone, L., Calautti, E., & Audrito, V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179985 · Cited by 31
Montali, I., Berti, C. C., Morselli, M., Acerbi, G., Barili, V., Pedrazzi, G., Montanini, B., Boni, C., Alfieri, A., Pesci, M., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.02.035 · Cited by 30
Byl, W. V. D., Nüssing, S., Peters, T. J., Ahn, A., Li, H., Ledergor, G., David, E., Koh, A. S., Wagle, M. V., Deguit, C. D. T., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.04.026 · Cited by 32
A Correlation Between Differentiation Phenotypes of Infused T Cells and Anti-Cancer Immunotherapy
Ren, H., Cao, K., & Wang, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.745109 · Cited by 30
“T Cell Exhaustion The transferred tumor-specific memory cells have become exhausted TILs with extensive heterogeneity in tamoxifeninduced autochthonous hepatocellular carcinoma (53) and fibrosarcoma (MCA205) (54) mice.”
BackgroundReprogramming responsiveness to checkpoint blockade in dysfunctional CD8 T cells
Nelson, C. E., Mills, L. J., McCurtain, J. L., Thompson, E. A., Seelig, D. M., Bhela, S., Quarnstrom, C. F., Fife, B. T., & Vezys, V. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1810326116 · Cited by 27
“(23) described this transcriptional profile as a state of fixed T cell dysfunction.”
BackgroundInfluentialMetabolic Control of Memory T-Cell Generation and StemnessPreprint
Raynor, J. L., Chapman, N. M., & Chi, H. (2021) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a037770 · Cited by 28
“Unlike PD-1+CD8+ exhausted T cells, TCF-1+CD8+ T cells may retain a chromatin state with the potential to reprogram in response to checkpoint blockade (Pauken et al. 2016; Scott-Browne et al. 2016; Ghoneim et al. 2017; Philip et al. 2017).”
BackgroundInfluentialZhao, X., Zhu, Y., He, Y., Gu, W., Zhou, Q., Jin, B., Chen, S., & Lin, H. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1597202 · Cited by 27
Integrative network modeling reveals mechanisms underlying T cell exhaustion
Bolouri, H., Young, M. H., Beilke, J. N., Johnson, R., Fox, B. A., Huang, L., Santini, C. C., Hill, C. M., de Vries, A.-R. V. D. V., Shannon, P. T., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-58600-8 · Cited by 27
Shin, H. M., Kim, G., Kim, S., Sim, J. H., Choi, J., Kim, M., Kwon, M., Ye, S.-K., Lee, D., Cho, S. W., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21299-w · Cited by 27
Veatch, J. R., Singhi, N., Srivastava, S., Szeto, J. L., Jesernig, B. L., Stull, S. M., Fitzgibbon, M., Sarvothama, M., Yechan-Gunja, S., James, S. E., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci144195 · Cited by 28
“This may be due to a deficiency in the breadth and number of tumor-reactive T cells (3) or irreversible dysfunction of these responses (4–6), raising the possibility that vaccination to augment preexisting tumor-reactive T cells or elicit new responses might improve outcomes when combined with ICIs.”
Stelekati, E., Cai, Z., Manne, S., Chen, Z., Beltra, J., Buchness, L. A., Leng, X., Ristin, S., Nzingha, K., Ekshyyan, V., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2106083119 · Cited by 24
Exhaustion of CD39-Expressing CD8+ T Cells in Crohn’s Disease Is Linked to Clinical Outcome
Globig, A.-M., Mayer, L., Heeg, M., Andrieux, G., Ku, M., Otto-Mora, P., Hipp, A. V., Zoldan, K., Pattekar, A., Rana, N., et al. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.06.045 · Cited by 30
Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming
Alvanou, M., Lysandrou, M., Christofi, P., Psatha, N., Spyridonidis, A., Παπαδοπούλου, Α., & Yannaki, E. (2023) · Cancers · doi:10.3390/cancers15071935 · Cited by 28
Yu, X., Yu, J., Dai, H., Deng, C., Sun, X., Long, S., Jiang, Z., Jin, H., Guan, Z., & Yang, Z. (2022) · Theranostics · doi:10.7150/thno.71010 · Cited by 26
“Here, the potential of cdG/Mix to reverse Tex within tumor and the systemic immune system in EO771 tumor-bearing mice was explored by detecting the expression of CD101 and CD38, which were recently identified as evidence of permanent T cell dysfunction [41,53].”
Stem-like CD8+ T cells in cancer
Steiner, C., Denlinger, N., Huang, X., & Yang, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1426418 · Cited by 28
Pembrolizumab in unresectable or metastatic MSI-high colorectal cancer: safety and efficacy
Roth, M., & Das, S. (2020) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2021.1851201 · Cited by 28
“Intrinsic T-cell deficits, such as epigenetic modification inducing T-cell exhaustion, may develop [49,50].”
BackgroundEpigenetic Regulation of Cancer Immune Cells
Patino, D. M. A., Radhakrishnan, V., Suvilesh, K. N., Manjunath, Y., Li, G., Kimchi, E. T., Staveley-O’Carroll, K. F., Warren, W. C., Kaifi, J. T., & Mitchem, J. B. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.06.022 · Cited by 26
Guo, H., Li, R., Wang, M., Hou, Y., Liu, S., Peng, T., Zhao, X., Lu, L., Han, Y., Shao, Y., et al. (2022) · Advanced Science · doi:10.1002/advs.202200978 · Cited by 25
Tumor-intrinsic metabolic reprogramming and how it drives resistance to anti-PD-1/PD-L1 treatment
Laubach, K., Turan, T., Mathew, R. S., Wilsbacher, J. L., Engelhardt, J., & Samayoa, J. A. (2023) · Cancer Drug Resistance · doi:10.20517/cdr.2023.60 · Cited by 27
Giorgioni, L., Ambrosone, A., Cometa, M. F., Salvati, A. L., Nisticò, R., & Magrelli, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251910365 · Cited by 27
“…independently of its ligand, a fifth-generation CAR construct has been recently reported. c-Kit c-Kit, also known as CD117, is a type-III receptor tyrosine kinase expressed in stem cell populations and essential for the development of several cell types such as erythrocytes and germ cells [42].”
BackgroundCD8+ T-cell exhaustion: Impediment to triple-negative breast cancer (TNBC) immunotherapy
Feng, D., Pu, D., Ren, J., Liu, M., Zhang, Z., Liu, Z., & Li, J. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189193 · Cited by 26
Colorectal Cancer at the Crossroads: The Good, the Bad, and the Future of Platinum-Based Drugs
Kee, J. X., Yau, J. N. N., Muthuramalingam, R. P. K., Wang, X., Chng, W. H., Lopez‐Sanchez, A., Tay, K. K. W., Deng, L., Gibson, D., Bertrand, H. C., et al. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.5c00041 · Cited by 29
Receptor signaling, transcriptional, and metabolic regulation of T cell exhaustion
Balkhi, M. Y. (2020) · OncoImmunology · doi:10.1080/2162402x.2020.1747349 · Cited by 26
Epigenetic Modifiers: Anti-Neoplastic Drugs With Immunomodulating Potential
Maes, K., Mondino, A., Lasarte, J. J., Agirre, X., Vanderkerken, K., Prósper, F., & Breckpot, K. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.652160 · Cited by 25
Eeckhout, B. V. D., Huyghe, L., Lint, S. V., Burg, E., Plaisance, S., Peelman, F., Cauwels, A., Uzé, G., Kley, N., Gerlo, S., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003293 · Cited by 25
New Immuno-oncology Targets and Resistance Mechanisms
Tokaz, M. C., Baik, C. S., Houghton, A. M., & Tseng, D. (2022) · Current Treatment Options in Oncology · doi:10.1007/s11864-022-01005-8 · Cited by 25
Blake, M. K., O’Connell, P. M., & Aldhamen, Y. A. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1082195 · Cited by 28
“Recent studies have demonstrated that T cell exhaustion is commonly associated with significant and unique genome-wide epigenetic remodeling programs which differentiate Tex cells from naïve, effector, and memory T cells (Pauken et al., 2016; Sen et al., 2016; Philip et al., 2017).”
BackgroundQuezada, L. K., Jin, W., Liu, Y. C., Kim, E. S., He, Z., Indralingam, C. S., Tysl, T., Labarta-Bajo, L., Wehrens, E. J., Jo, Y., et al. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3001983 · Cited by 24
SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis
Xie, Y., Şahin, M., Wakamatsu, T., Inoue‐Yamauchi, A., Zhao, W., Han, S., Nargund, A. M., Yang, S., Lyu, Y., Hsieh, J. J.-D., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.154120 · Cited by 22
“The annotation of the atlas and differential accessibility analysis of the peaks was performed as previously described (57).”
MethodSelf-citationSingh, S. D., Singh, N., Baranwal, M., Sharma, S., Devi, S., & Kumar, S. (2023) · 3 Biotech · doi:10.1007/s13205-023-03826-2 · Cited by 24
“In addition, PD-1 blockade induces transcriptional alterations associated with effector T cells in TEX cells but not memory T cells (Philip et al. 2017).”
BackgroundLi, M., Jiang, A., Han, H., Chen, M., Wang, B., Cheng, Y., Zhang, H., Wang, X., Dai, W., Yang, W., et al. (2023) · ACS Nano · doi:10.1021/acsnano.3c03352 · Cited by 24
Phenotypic and spatial heterogeneity of CD8+ tumour infiltrating lymphocytes
Sun, Y., Yinwang, E., Wang, S., Wang, Z., Wang, F., Xue, Y., Zhang, W., Zhao, S., Mou, H., Chen, S., et al. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02104-w · Cited by 29
“…of exhaustion (loss of effector function, upregulation of immune checkpoint molecules, and contracted proliferative capacity) are regulated independently and ripen asynchronously [86–88], where, for instance, IFN-γ and TNF loss preceded that of proliferative capacity by a large margin [86].”
BackgroundInfluentialUllrich, F., Bröckelmann, P. J., Turki, A. T., Khan, A., Chiru, E.-D., Vetter, M. H. F., von Tresckow, B., Wirth, R., Córdoba, R., Ortiz‐Maldonado, V., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009462 · Cited by 25
The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion
Dahabieh, M. S., DeCamp, L. M., Oswald, B. M., Kitchen-Goosen, S. M., Fu, Z. F., Vos, M., Compton, S. E., Longo, J., Foy, N. M., Williams, K. S., et al. (2025) · Nature Immunology · doi:10.1038/s41590-025-02185-9 · Cited by 24
Molecular Chaperones: Molecular Assembly Line Brings Metabolism and Immunity in Shape
Zhao, H., Raines, L. N., & Huang, S. C. (2020) · Metabolites · doi:10.3390/metabo10100394 · Cited by 24
“Studies have indicated that the differentiation and activation of immune cells requires tight regulation of gene expression governed by epigenetic programs [34,35].”
Immune Modulation in Lung Cancer: Current Concepts and Future Strategies
Gaissmaier, L., & Christopoulos, P. (2020) · Respiration · doi:10.1159/000510385 · Cited by 24
Fu, J., Yu, A., Xiao, X., Tang, J., Zu, X., Chen, W., & He, B. (2020) · PubMed · Cited by 31
Zhang, H., Wu, J., Zou, D., Xiao, X., Yan, H., Li, X. C., & Chen, W. (2018) · American Journal of Transplantation · doi:10.1111/ajt.15196 · Cited by 24
Neuropilin-1: A Multifaceted Target for Cancer Therapy
Varanasi, S. M., Gulani, Y., Rachamala, H. K., Mukhopadhyay, D., & Angom, R. S. (2025) · Current Oncology · doi:10.3390/curroncol32040203 · Cited by 25
“Sema3A is produced in cancer cells and dysfunctional tumor-specific CD8+ T cells and can modulate anti-tumor response by upregulating NRP1, such as PD-1 [105,107,108].”
Thrombospondin-1–CD47 signaling contributes to the development of T cell exhaustion in cancer
Weng, C., Assouvie, A., Dong, L., Beltra, J., Budhu, S., Mangarin, L. M. B., Marouf, Y., Morgado-Palacin, L., Liu, C., Monette, S., et al. (2025) · Nature Immunology · doi:10.1038/s41590-025-02321-5 · Cited by 24
Self-citationT Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities
Yang, Y. P., Yao, X., Wang, Q., Yang, M., Li, R., Qin, J., Zhuang, J., & Sun, C. (2026) · Advanced Science · doi:10.1002/advs.202520634 · Cited by 27
Pietro, A. D., & Good‐Jacobson, K. L. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1800137 · Cited by 24
“Analysis of chromatin accessibility using Assay for Transposase-Accessible Chromatin using sequencing profiles has revealed that almost 50% of chromatin-accessible regions were differently present in exhausted CD8 T cells during chronic lymphocytic choriomeningitis infection or in tumor models compared with functional…”
BackgroundMethodYu, H., Hong, X., Wu, H., Zheng, F., Zeng, Z., Dai, W., Yin, L., Liu, D. J., Tang, D., & Dai, Y. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.641886 · Cited by 23
“Since chromatin accessibility plays a vital role in gene regulation and genome stability, and since changes in chromatin accessibility patterns may alter the accessibility of the genome’s regulatory regions to critical proteins, chromatin accessibility patterns are emerging as an essential component of human diseases…”
BackgroundCD38–RyR2 axis–mediated signaling impedes CD8 + T cell response to anti-PD1 therapy in cancer
Kar, A., Ghosh, P., Gautam, A., Chowdhury, S., Basak, D., Sarkar, I., Bhoumik, A., Barman, S., Chakraborty, P., Mukhopadhyay, A., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2315989121 · Cited by 23
“This finding aligns with previous reports placing CD38 in intratumoral T cell subsets that display terminal differentiation and incapability for functional rejuvenation (9, 17, 18).”
Tooley, K., Jerby‐Arnon, L., Escobar, G., Krovi, S. H., Mangani, D., Dandekar, G., Cheng, H., Madi, A., Goldschmidt, E., Lambden, C., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101640 · Cited by 29
Prediction of cancer neoepitopes needs new rules
Brennick, C. A., George, M. M., Srivastava, P. K., & Karandikar, S. H. (2020) · Seminars in Immunology · doi:10.1016/j.smim.2020.101387 · Cited by 22
Toward Systems Biomarkers of Response to Immune Checkpoint Blockers
Lapuente-Santana, Ó., & Eduati, F. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01027 · Cited by 23
Remodeling the tumor dormancy ecosystem to prevent recurrence and metastasis
Liang, Y., Chen, W., Zhang, Y., & Li, L. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02328-2 · Cited by 29
Luo, H., Wang, W., Mai, J., Yin, R., Cai, X., & Li, Q. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1267918 · Cited by 22
Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness
Lin, C., Levy, P. L., Alflen, A., Apriamashvili, G., Ligtenberg, M. A., Vredevoogd, D. W., Bleijerveld, O. B., Alkan, F., Malka, Y., Hoekman, L., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.02.016 · Cited by 21
Overcoming Resistance Mechanisms to Melanoma Immunotherapy
Zheng, D. X., Bozym, D. J., Tarantino, G., Sullivan, R. J., Liu, D., & Jenkins, R. W. (2024) · American Journal of Clinical Dermatology · doi:10.1007/s40257-024-00907-7 · Cited by 25
Reticker-Flynn, N. E., & Engleman, E. G. (2020) · eLife · doi:10.7554/elife.53839 · Cited by 23
Modulation of T cell function and survival by the tumor microenvironment
Mani, N. L., Andrews, D., & Obeng, R. C. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1191774 · Cited by 22
“This programming cannot be overridden by using immune checkpoint inhibition to drive the differentiation of new effector progeny (Utzschneider et al., 2013; Pauken et al., 2016; Ghoneim et al., 2017; Philip et al., 2017).”
BackgroundJeon, S. H., Song, C., Eom, K., Kim, I. A., & Js, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316691 · Cited by 21
“The exhaustion process cannot be reversed due to their epigenetically fixed status [14].”
BackgroundBecker, W., Olkhanud, P. B., Seishima, N., Moreno, P. A., Goldfarbmuren, K. C., Maeng, H. M., & Berzofsky, J. A. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-008970 · Cited by 21
Ebelt, N., Zuniga, E., Marzagalli, M., Zamloot, V., Blazar, B., Salgia, R., & Manuel, E. R. (2020) · Biomedicines · doi:10.3390/biomedicines8120617 · Cited by 21
“Fully tolerized, self T cells—which share a very similar transcriptional profile to fixed, dysfunctional, tumor-specific T cells [70]—are completely resistant to single target checkpoint blockade treatment as well as the combination of anti-CTLA-4 and anti-PD-1.”
Zhou, J., Wang, W., Liang, Z., Ni, B., He, W., & Wang, D. (2020) · Oncology Letters · doi:10.3892/ol.2020.11580 · Cited by 20
“to secrete IFN-γ and TNF-α following in vitro stimulation to kill tumors, and that CD8+ T cells in state 2 strongly coexpress CD38 and CD101, and lose their ability to secrete IFN-γ and TNF-α despite several rounds of stimulation (8).”
Influentialden Berge, K. V., Chou, H.-J., de Bézieux, H. R., Street, K., Risso, D., Ngai, J., & Dudoit, S. (2022) · Cell Reports Methods · doi:10.1016/j.crmeth.2022.100321 · Cited by 19
“4.5 Case studies 4.5.1 Mouse Tissue Atlas The raw count matrix from Liu et al. 30 is obtained as described in the Datasets section and is normalized using each of the twelve evaluated normalization procedures, with no peaks filtered out.”
BackgroundMethodInfluentialChimeric antigen receptor T-cell therapy for multiple myeloma
Wang, Z., Chen, C., Wang, L., Jia, Y., & Qin, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1050522 · Cited by 21
Sarén, T., Ramachandran, M., Gammelgård, G., Lövgren, T., Mirabello, C., Björklund, Å. K., Wikstrom, K. I., Hashemi, J., Freyhult, E., Ahlström, H. K., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-0178 · Cited by 19
Feng, M., Liu, X., Hao, X., Ren, Y., Dong, G., Tian, J., Wang, Y., Du, L., Wang, Y., & Wang, C. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-0287 · Cited by 21
T cell landscape in the microenvironment of human solid tumors
Maggi, E., Munari, E., Landolina, N., Mariotti, F. R., Azzarone, B. G., & Moretta, L. (2024) · Immunology Letters · doi:10.1016/j.imlet.2024.106942 · Cited by 22
Cancer and HIV-1 Infection: Patterns of Chronic Antigen Exposure
Viganó, S., Bobisse, S., Coukos, G., Perreau, M., & Harari, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01350 · Cited by 21
“Comprehensive whole-genome analysis of chromatin accessibility (ATAC-seq) (206), has shown that exhausted CD8T cells have a distinct epigenetic signature (95, 109, 111, 112, 207, 208).”
BackgroundMethodInfluentialMa, K., Sun, L., Shen, M., Zhang, X., Xiao, Z., Wang, J., Liu, X., Jiang, K., Qin, F. X.-F., Guo, F., et al. (2022) · iScience · doi:10.1016/j.isci.2022.104347 · Cited by 20
“As one of the well-known NAD+ consuming enzymes, CD38 was positively correlated with the dysfunctionality of CD8+ T cells in the tumor (Philip et al., 2017; Verma et al., 2019).”
BackgroundResultInfluentialSelf-citation(2017) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-017-0297-3 · Cited by 20
Multiparametric analysis of colorectal cancer immune responses
Leman, J. K. H., Sandford, S., Rhodes, J. L., & Kemp, R. A. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i27.2995 · Cited by 19
Enhancing the Efficacy of Tumor Vaccines Based on Immune Evasion Mechanisms
Chen, J., Zhang, H., Zhou, L., Hu, Y., Li, M., He, Y., & Li, Y. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.584367 · Cited by 19
“The blockade of PD1 under sub-optimally activated CD8 T cell conditions would lead to the presence of dysfunctional PD-1CD38CD8 T cells, resulting in the failure of antigenic stimulation response and defective effector functions (111).”
BackgroundNew Developments in T Cell Immunometabolism and Implications for Cancer Immunotherapy
Oberholtzer, N. P., Quinn, K. M., Chakraborty, P., & Mehrotra, S. (2022) · Cells · doi:10.3390/cells11040708 · Cited by 19
“The other is a fixed dysfunctional state that renders T cells resistant to reprogramming [235].”
BackgroundHöllbacher, B., Balázs, K., Heinig, M., & Uhlenhaut, N. H. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.05.018 · Cited by 20
New cytometry tools for immune monitoring during cancer immunotherapy
Sanjabi, S., & Lear, S. P. (2021) · Cytometry Part B Clinical Cytometry · doi:10.1002/cyto.b.21984 · Cited by 20
“The exhausted progenies become epigenetically remodeled and eventually resistant to ICB antibodies (Philip et al., 2017).”
BackgroundWeber, E. W., Lynn, R. C., Parker, K. R., Anbunathan, H., Lattin, J., Sotillo, E., Good, Z., Malipatlolla, M., Xu, P., Vandris, P., et al. (2020) · doi:10.1101/2020.01.26.920496 · Cited by 18
“Similarly, murine tumor models have revealed that exhaustion reprogrammability is associated with increased accessibility at the Tcf7 locus (Philip et al., 2017).”
BackgroundInfluentialHaku, Y., Kitaoka, K., Ichimaru, K., Hirano, T., Wang, J., Sonomura, K., Maruo, A., Hirose, S., Wang, Y., Ito, K., et al. (2026) · Nature Immunology · doi:10.1038/s41590-025-02370-w · Cited by 19
Methio “mine”! Cancer cells steal methionine and impair CD8 T‐cell function
Gubser, P. M., & Kallies, A. (2020) · Immunology and Cell Biology · doi:10.1111/imcb.12385 · Cited by 18
“” These functional changes are also reflected by epigenetic modifications at gene loci encoding effector molecules, including interferon-c and granzymes.(1) Checkpoint inhibition, such as PD-1/PD-L1 blockade, can activate exhausted CD8 T cells and has revolutionized cancer therapy in the past decade.”
BackgroundTargeting Neoepitopes to Treat Solid Malignancies: Immunosurgery
de Sousa, E., Lérias, J. R., Antonio Lopez-beltran, B., Paraschoudi, G., Condeço, C., Kamiki, J., António, P., Figueiredo, N., Carvalho, C. T., Castillo-Martín, M., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.592031 · Cited by 17
The TOX subfamily: all-round players in the immune system
Han, J., Wan, M., Ma, Z., & He, P. (2022) · Clinical & Experimental Immunology · doi:10.1093/cei/uxac037 · Cited by 18
Application of ATAC-seq in tumor-specific T cell exhaustion
Chen, C., Liu, J., Chen, Y., Lin, A., Mou, W., Zhu, L., Yang, T., Cheng, Q., Zhang, J., & Luo, P. (2022) · Cancer Gene Therapy · doi:10.1038/s41417-022-00495-w · Cited by 19
“Meanwhile, after inhibiting NFAT with calcineurin inhibitor FK506 [19, 61, 62], there was a decrease in the expression of TOX and PD-1 in Tex, while the level of TCF-1 was increased.”
BackgroundMethodImmune Checkpoint Molecules and Glucose Metabolism in HIV-Induced T Cell Exhaustion
Chan, Y. T., Cheong, H. C., Tang, T. F., Rajasuriar, R., Cheng, K., Looi, C. Y., Wong, W. F., & Kamarulzaman, A. (2022) · Biomedicines · doi:10.3390/biomedicines10112809 · Cited by 19
Proteomics of immune cells from liver tumors reveals immunotherapy targets
Canale, F. P., Neumann, J., von Renesse, J., Loggi, E., Pecoraro, M., Vogel, I. A., Zoppi, G., Antonini, G., Wolf, T., Jin, W., et al. (2023) · Cell Genomics · doi:10.1016/j.xgen.2023.100331 · Cited by 18
LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8+ T cell responsiveness
Pallavicini, I., Frasconi, T. M., Catozzi, C., Ceccacci, E., Tiberti, S., Haas, D., Samson, J., Heuser-Loy, C., Lauson, C. B. N., Mangione, M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51500-9 · Cited by 19
“Tcells mayresist current strategies for reversing T cell exhaustion as a result of stable changesingeneregulationduetoepigeneticreprogramming 22,23,63 .”
Distinct Graft-Specific TCR Avidity Profiles during Acute Rejection and Tolerance
Miller, M. L., Mcintosh, C. M., Williams, J. B., Wang, Y., Hollinger, M. K., Isaad, N. J., Moon, J. J., Gajewski, T. F., Chong, A. S., & Alegre, M. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.067 · Cited by 18
“For these other specificities, resistance to avidity maturation may be epigenetically imprinted, similar to T cell-intrinsic hyporesponsiveness, which makes cells resistant to secondary encounter of antigen (Philip et al., 2017; Schietinger et al., 2012), or may be constrained by regulatory cells distinct from classic…”
BackgroundNew targets and technologies for CAR-T cells
Freitag, F., Maucher, M., Riester, Z., & Hudecek, M. (2020) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000653 · Cited by 20
“T-cell exhaustion has been identified as one major cause that limits the efficacy of CAR-T cell therapy in solid tumors [35].”
BackgroundXGSEA: CROSS-species gene set enrichment analysis via domain adaptation
Cai, M., Nguyen, C. H., Mamitsuka, H., & Li, L. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa406 · Cited by 16
Pace, L. (2021) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a037754 · Cited by 19
The role of CD8+ T-cells in colorectal cancer immunotherapy
He, T., Hu, C., Li, S., Fan, Y., Xie, F., Sun, X., Jiang, Q., Chen, W., Jia, Y., & Li, W. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e33144 · Cited by 20
“In chronic infection, when the duration lasts 2 – 3 weeks, the molecular program of exhaustion is established [80].”
BackgroundYang, Y., Li, X., Liu, F., Ma, M., Yang, Y., Ruan, C., Lü, Y., Li, X., Wang, X., Shi, Y., et al. (2025) · JCI Insight · doi:10.1172/jci.insight.174600 · Cited by 19
“Interestingly, CD8 + tumor-infiltrating lymphocytes (TILs) undergo progressive changes in chromatin architecture during the development of T cell exhaustion, as demonstrated by recent studies (8–10).”
Immune correlates and mechanisms of TIL therapy efficacy: current insights and knowledge gaps
Rodrigo, B. N., Ortiz-Miranda, Y., Corría-Osorio, J., Coukos, G., & Harari, A. (2025) · Trends in cancer · doi:10.1016/j.trecan.2025.08.002 · Cited by 22
The ubiquitin ligase KLHL6 drives resistance to CD8+ T cell dysfunction
Cheng, H., Su, Y., Pan, X., Xu, Y., Xie, E., Du, J., Chen, D. G., Dai, X., Gottardo, R., Greenberg, P. D., et al. (2026) · Nature · doi:10.1038/s41586-025-09926-8 · Cited by 18
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
