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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Both Slco3a1 and Abcb1a were significantly down-regulated in exhausted CD8+ T cells relative to effector cells.
“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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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 · see citing works
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Self-citationBuenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., & Greenleaf, W. J. (2013) · Nature Methods · doi:10.1038/nmeth.2688 · Cited by 6,422 · see citing works
GREAT improves functional interpretation of cis-regulatory regions
McLean, C. Y., Bristor, D., Hiller, M., Clarke, S. L., Schaar, B. T., Lowe, C. B., Wenger, A. M., & Bejerano, G. (2010) · Nature Biotechnology · doi:10.1038/nbt.1630 · Cited by 4,502 · see citing works
Software for Computing and Annotating Genomic Ranges
Lawrence, M. F., Huber, W. K., Pagès, H., Aboyoun, P., Carlson, M. R. J., Gentleman, R. C., Morgan, M. T., & Carey, V. J. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003118 · Cited by 4,438 · see citing works
Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma
Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J. M., Desrichard, A., Walsh, L. A., Postow, M. A., Wong, P., Ho, T. S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1406498 · Cited by 4,286 · see citing works
Self-citationFIMO: scanning for occurrences of a given motif
Grant, C. E., Bailey, T. L., & Noble, W. S. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr064 · Cited by 4,247 · see citing works
Determination and Inference of Eukaryotic Transcription Factor Sequence Specificity
Weirauch, M. T., Yang, A. W. H., Albu, M., Coté, A. G., Montenegro‐Montero, A., Drewe, P., Najafabadi, H. S., Lambert, S. A., Mann, I. K., Cook, K. B., et al. (2014) · Cell · doi:10.1016/j.cell.2014.08.009 · Cited by 1,705 · see citing works
The UCSC Genome Browser Database: update 2006
Hinrichs, A. S. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkj144 · Cited by 1,646 · see citing works
Transcriptional control of effector and memory CD8+ T cell differentiation
Kaech, S. M., & Cui, W. (2012) · Nature Reviews Immunology · doi:10.1038/nri3307 · Cited by 1,628 · see citing works
NFAT proteins: key regulators of T-cell development and function
Macián, F. (2005) · Nature reviews. Immunology · doi:10.1038/nri1632 · Cited by 1,575 · see citing works
Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., Drake, A. M., Chen, Z., Sen, D. R., Kurachi, M., et al. (2016) · Science · doi:10.1126/science.aaf2807 · Cited by 1,348 · see citing works
The future of cancer treatment: immunomodulation, CARs and combination immunotherapy
Khalil, D. N., Smith, E. L., Brentjens, R. J., & Wolchok, J. D. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.25 · Cited by 1,150 · see citing works
Self-citationNuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A
Flanagan, W. M., Corthésy, B., Bram, R. J., & Crabtree, G. R. (1991) · Nature · doi:10.1038/352803a0 · Cited by 1,057 · see citing works
Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells
Gattinoni, L., Zhong, X.-S., Palmer, D. C., Ji, Y., Hinrichs, C. S., Yu, Z., Wrzesinski, C., Boni, A., Cassard, L., Garvin, L. M., et al. (2009) · Nature Medicine · doi:10.1038/nm.1982 · Cited by 1,031 · see citing works
The epigenetic landscape of T cell exhaustion
Sen, D. R., Kaminski, J., Barnitz, R. A., Kurachi, M., Gerdemann, U., Yates, K. B., Tsao, H.-W., Godec, J., LaFleur, M. W., Brown, F. D., et al. (2016) · Science · doi:10.1126/science.aae0491 · Cited by 986 · see citing works
The Transcription Factor NFAT Promotes Exhaustion of Activated CD8 + T Cells
Martinez, G. J., Pereira, R. M., Äijö, T., Kim, E. Y., Marangoni, F., Pipkin, M. E., Togher, S., Heissmeyer, V., Zhang, Y. C., Crotty, S., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.01.006 · Cited by 857 · see citing works
Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism
Peng, M., Yin, N., Chhangawala, S., Xu, K., Leslie, C. S., & Li, M. O. (2016) · Science · doi:10.1126/science.aaf6284 · Cited by 787 · see citing works
Self-citationThe T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun
Jain, J., McCaffrey, P. G., Miner, Z., Kerppola, T. K., Jn, L., Verdine, G. L., Curran, T., & Rao, A. (1993) · Nature · doi:10.1038/365352a0 · Cited by 768 · see citing works
Schietinger, A., Philip, M., Krisnawan, V. E., Chiu, E. Y., Delrow, J. J., Basom, R. S., Lauer, P., Brockstedt, D. G., Knoblaugh, S. E., Hämmerling, G. J., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.011 · Cited by 720 · see citing works
Self-citationAdey, A., Morrison, H. G., Asan, Xu, X., Kitzman, J. O., Turner, E. H., Stackhouse, B., MacKenzie, A. P., Caruccio, N. C., Zhang, X., et al. (2010) · Genome biology · doi:10.1186/gb-2010-11-12-r119 · Cited by 566 · see citing works
Ki-67 acts as a biological surfactant to disperse mitotic chromosomes
Cuylen‐Haering, S., Blaukopf, C., Politi, A. Z., Müller‐Reichert, T., Neumann, B., Poser, I., Ellenberg, J., Hyman, A. A., & Gerlich, D. W. (2016) · Nature · doi:10.1038/nature18610 · Cited by 550 · see citing works
Cellular and Humoral immunity to Different Types of Human Neoplasms
Hellström, I., Hellström, K. E., Pierce, G. E., & Yang, J. P. S. (1968) · Nature · doi:10.1038/2201352a0 · Cited by 394 · see citing works
Zhang, J. A., Mortazavi, A., Williams, B. A., Wold, B. J., & Rothenberg, E. V. (2012) · Cell · doi:10.1016/j.cell.2012.01.056 · Cited by 337 · see citing works
Transcriptional insights into the CD8+ T cell response to infection and memory T cell formation
Best, J., Blair, D., Knell, J., Yang, E., Mayya, V., Doedens, A. L., Dustin, M. L., & Goldrath, A. W. (2013) · Nature Immunology · doi:10.1038/ni.2536 · Cited by 334 · see citing works
Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality
Shih, H.-Y., Sciumè, G., Mikami, Y., Guo, L., Sun, H.-W., Brooks, S. R., Urban, J. F., Davis, F. P., Kanno, Y., & O’Shea, J. J. (2016) · Cell · doi:10.1016/j.cell.2016.04.029 · Cited by 334 · see citing works
Dynamic Changes in Chromatin Accessibility Occur in CD8 + T Cells Responding to Viral Infection
Scott-Browne, J. P., López-Moyado, I. F., Trifari, S., Wong, V., Chávez, L., Rao, A., & Pereira, R. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.10.028 · Cited by 313 · see citing works
Listeria -based cancer vaccines that segregate immunogenicity from toxicity
Brockstedt, D. G., Giedlin, M. A., Leong, M. L. L., Bahjat, K. S., Gao, Y. Q., Luckett, W. S., Liu, W., Cook, D. N., Portnoy, D. A., & Dubensky, T. W. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0406035101 · Cited by 299 · see citing works
Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors
Teague, R. M., Sather, B. D., Sacks, J. A., Huang, M. Z., Dossett, M. L., Morimoto, J. O., Tan, X., Sutton, S. E., Cooke, M. P., Öhlén, C., et al. (2006) · Nature Medicine · doi:10.1038/nm1359 · Cited by 233 · see citing works
Russ, B. E., Olshanksy, M., Smallwood, H. S., Li, J., Denton, A. E., Prier, J. E., Stock, A. T., McQuilten, H. A., Cullen, J. G., Nguyen, M. L. T., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.11.001 · Cited by 222 · see citing works
Global DNA Methylation Remodeling Accompanies CD8 T Cell Effector Function
Scharer, C. D., Barwick, B. G., Youngblood, B., Ahmed, R., & Boss, J. M. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301395 · Cited by 207 · see citing works
Acquired and intrinsic resistance in cancer immunotherapy
Kelderman, S., Schumacher, T. N. M., & Haanen, J. B. A. G. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.07.011 · Cited by 197 · see citing works
Araki, Y., Fann, M., Wersto, R. P., & Weng, N. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.12.8102 · Cited by 188 · see citing works
Rescued Tolerant CD8 T Cells Are Preprogrammed to Reestablish the Tolerant State
Schietinger, A., Delrow, J. J., Basom, R., Blattman, J. N., & Greenberg, P. D. (2012) · Science · doi:10.1126/science.1214277 · Cited by 172 · see citing works
Self-citationRelapse or Eradication of Cancer Is Predicted by Peptide-Major Histocompatibility Complex Affinity
Engels, B., Engelhard, V. H., Sidney, J., Sette, A., Binder, D. C., Liu, R. B., Kranz, D. M., Meredith, S. C., Rowley, D. A., & Schreiber, H. W. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.03.018 · Cited by 149 · see citing works
Denton, A. E., Russ, B. E., Doherty, P. C., Rao, S., & Turner, S. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112520108 · Cited by 99 · see citing works
Li, Y., Liu, S., Hernandez, J., Vence, L. M., Hwu, P., & Radvanyi, L. G. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901101 · Cited by 97 · see citing works
Staveley-O’Carroll, K. F., Schell, T. D., Jimenez, M., Mylin, L. M., Tevethia, M. J., Schoenberger, S. P., & Tevethia, S. S. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.2.697 · Cited by 79 · see citing works
Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution
Denas, O., Sandstrom, R. S., Cheng, Y., Beal, K. M., Herrero, J., Hardison, R. C., & Taylor, J. (2015) · BMC Genomics · doi:10.1186/s12864-015-1245-6 · Cited by 63 · see citing works
Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
Waugh, K. A., Leach, S. M., Moore, B. L., Bruno, T. C., Buhrman, J. D., & Slansky, J. E. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600589 · Cited by 58 · see citing works
Sinnathamby, G., Lauer, P., Zerfass, J., Hanson, B., Karabudak, A., Krakover, J. D., Secord, A. A., Clay, T. M., Morse, M. A., Dubensky, T. W., et al. (2009) · Journal of Immunotherapy · doi:10.1097/cji.0b013e3181b0b125 · Cited by 31 · see citing works
Self-citationStahl, S. H., Sacher, T., Bechtold, A., Protzer, U., Ganß, R., Hämmerling, G. J., Arnold, B., & Garbi, N. (2009) · Immunology Letters · doi:10.1016/j.imlet.2009.01.011 · Cited by 26 · see citing works
Zigler, C. M., & Belin, T. R. (2011) · The Annals of Applied Statistics · doi:10.1214/11-aoas477 · Cited by 11 · see citing works
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Understanding the tumor immune microenvironment (TIME) for effective therapy
Binnewies, M., Roberts, E. W., Kersten, K., Chan, V., Fearon, D. F., Merad, M., Coussens, L. M., Gabrilovich, D. I., Ostrand-Rosenberg, S., Hedrick, C. C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0014-x · Cited by 6,145 · see citing works
Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response
Jiang, P., Gu, S., Pan, D., Fu, J., Sahu, A., Hu, X., Li, Z., Traugh, N., Bu, X., Li, B., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0136-1 · Cited by 5,179 · see citing works
Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
Wei, S. C., Duffy, C. R., & Allison, J. P. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0367 · Cited by 3,088 · see citing works
Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma
Sade-Feldman, M., Yizhak, K., Bjorgaard, S. L., Ray, J. P., de Boer, C. G., Jenkins, R. W., Lieb, D. J., Chen, J. H., Frederick, D. T., Barzily-Rokni, M., et al. (2018) · Cell · doi:10.1016/j.cell.2018.10.038 · Cited by 2,053 · see citing works
“Finally, we compared open chromatin in DP and DN cells to those of recently reported dysfunctional PD-1CD8 cells and central memory cells (CD45RA CD45ROCD62L) (Philip et al., 2017).”
InfluentialMiller, B. C., Sen, D. R., Al Abosy, R., Bi, K., Virkud, Y. V., LaFleur, M. W., Yates, K. B., Lako, A., Felt, K., Naik, G. S., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0312-6 · Cited by 2,087 · see citing works
Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment
Azizi, E., Carr, A. J., Plitas, G., Cornish, A. E., Konopacki, C., Prabhakaran, S., Nainys, J., Wu, K., Kiseliovas, V., Setty, M., et al. (2018) · Cell · doi:10.1016/j.cell.2018.05.060 · Cited by 1,976 · see citing works
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer
McLane, L. M., Abdel-Hakeem, M. S., & Wherry, E. J. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-041015-055318 · Cited by 1,973 · see citing works
TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion
Khan, O., Giles, J. R., McDonald, S., Manne, S., Ngiow, S. F., Patel, K. P., Werner, M. T., Huang, A. C., Alexander, K. A., Wu, J. E., et al. (2019) · Nature · doi:10.1038/s41586-019-1325-x · Cited by 1,646 · see citing works
Blank, C. U., Haining, W. N., Held, W., Hogan, P. G., Kallies, A., Lugli, E., Lynn, R. C., Philip, M., Rao, A., Restifo, N. P., et al. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0221-9 · Cited by 1,603 · see citing works
Self-citationEngineering strategies to overcome the current roadblocks in CAR T cell therapy
Rafiq, S., Hackett, C. S., & Brentjens, R. J. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0297-y · Cited by 1,477 · see citing works
“For example, disease-related dysfunctions of T cells 217 , such as those described in patients with CLL 218,219 or solid tumours 220 , can result in unsuccessful manufacturing or inferior products that lead to poor response rates in patients.”
BackgroundMechanisms of resistance to immune checkpoint inhibitors
Jenkins, R. W., Barbie, D. A., & Flaherty, K. T. (2018) · British Journal of Cancer · doi:10.1038/bjc.2017.434 · Cited by 1,383 · see citing works
Hiam-Galvez, K. J., Allen, B. M., & Spitzer, M. H. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-021-00347-z · Cited by 1,400 · see citing works
Thommen, D. S., & Schumacher, T. N. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.012 · Cited by 1,304 · see citing works
“E urope PM C Funders A uthor M anuscripts E urope PM C Funders A uthor M anuscripts (Philip et al., 2017).”
BackgroundLi, H., van der Leun, A. M., Yofe, I., Lubling, Y., Gelbard-Solodkin, D., van Akkooi, A. C. J., van den Braber, M., Rozeman, E. A., Haanen, J. B. A. G., Blank, C. U., et al. (2019) · Cell · doi:10.1016/j.cell.2018.11.043 · Cited by 1,101 · see citing works
TOX is a critical regulator of tumour-specific T cell differentiation
Scott, A. C., Dündar, F., Zumbo, P., Chandran, S. S., Klebanoff, C. A., Shakiba, M., Trivedi, P., Menocal, L., Appleby, H., Camara, S., et al. (2019) · Nature · doi:10.1038/s41586-019-1324-y · Cited by 1,106 · see citing works
Self-citationBeltra, J., Manne, S., Abdel-Hakeem, M. S., Kurachi, M., Giles, J. R., Chen, Z., Casella, V., Ngiow, S. F., Khan, O., Huang, Y., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.04.014 · Cited by 1,091 · see citing works
A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments
Barry, K. C., Hsu, J., Broz, M. L., Cueto, F. J., Binnewies, M., Combes, A. J., Nelson, A. E., Loo, K., Kumar, R., Rosenblum, M. D., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0085-8 · Cited by 1,021 · see citing works
CD8+ T cell differentiation and dysfunction in cancer
Philip, M., & Schietinger, A. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00574-3 · Cited by 1,052 · see citing works
Self-citationAdvances in the development of personalized neoantigen-based therapeutic cancer vaccines
Blass, E., & Ott, P. A. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-00460-2 · Cited by 1,042 · see citing works
Sun, L., Su, Y., Jiao, A., Wang, X., & Zhang, B. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01471-y · Cited by 1,057 · see citing works
Self-citationClinical implications of T cell exhaustion for cancer immunotherapy
Chow, A., Perica, K., Klebanoff, C. A., & Wolchok, J. D. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00689-z · Cited by 1,044 · see citing works
Self-citationCo-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors
Duhen, T., Duhen, R., Montler, R., Moses, J., Moudgil, T., de Miranda, N. F., Goodall, C. P., Blair, T. C., Fox, B. A., McDermott, J. E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05072-0 · Cited by 938 · see citing works
Immune-checkpoint inhibitors: long-term implications of toxicity
Johnson, D. B., Nebhan, C. A., Moslehi, J. J., & Balko, J. M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00600-w · Cited by 982 · see citing works
Satpathy, A. T., Granja, J. M., Yost, K. E., Qi, Y., Meschi, F., McDermott, G. P., Olsen, B. N., Mumbach, M. R., Pierce, S. E., Corces, M. R., et al. (2019) · Nature Biotechnology · doi:10.1038/s41587-019-0206-z · Cited by 980 · see citing works
The cancer-immunity cycle: Indication, genotype, and immunotype
Mellman, I., Chen, D. S., Powles, T. B., & Turley, S. J. (2023) · Immunity · doi:10.1016/j.immuni.2023.09.011 · Cited by 978 · see citing works
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Lynn, R. C., Weber, E. W., Sotillo, E., Gennert, D., Xu, P., Good, Z., Anbunathan, H., Lattin, J., Jones, R., Tieu, V., et al. (2019) · Nature · doi:10.1038/s41586-019-1805-z · Cited by 891 · see citing works
Scharping, N. E., Rivadeneira, D. B., Menk, A. V., Vignali, P. D. A., Ford, B. R., Rittenhouse, N. L., Peralta, R., Wang, Y., Wang, Y., DePeaux, K., et al. (2021) · Nature Immunology · doi:10.1038/s41590-020-00834-9 · Cited by 897 · see citing works
TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection
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Chen, J., López-Moyado, I. F., Seo, H., Lio, C.-W. J., Hempleman, L. J., Sekiya, T., Yoshimura, A., Scott-Browne, J. P., & Rao, A. (2019) · Nature · doi:10.1038/s41586-019-0985-x · Cited by 874 · see citing works
Chemokines and the immune response to cancer
Ozga, A. J., Chow, M. T., & Luster, A. D. (2021) · Immunity · doi:10.1016/j.immuni.2021.01.012 · Cited by 846 · see citing works
Turning Cold into Hot: Firing up the Tumor Microenvironment
Duan, Q., Zhang, H., Zheng, J., & Zhang, L. (2020) · Trends in Cancer · doi:10.1016/j.trecan.2020.02.022 · Cited by 934 · see citing works
Seo, H., Chen, J., González-Avalos, E., Samaniego-Castruita, D., Das, A., Wang, Y. H., López-Moyado, I. F., Georges, R. O., Zhang, W., Onodera, A., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1905675116 · Cited by 808 · see citing works
Xu, S., Chaudhary, O., Rodríguez-Morales, P., Sun, X., Chen, D., Zappasodi, R., Xu, Z. Z., Pinto, A. F. M., Williams, A. E., Schulze, I., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.05.003 · Cited by 815 · see citing works
Self-citationZhang, Y., Chen, H., Mo, H., Hu, X., Gao, R., Zhao, Y., Liu, B., Niu, L., Sun, X., Yu, X., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.09.010 · Cited by 783 · see citing works
Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer
Oh, D. Y., Kwek, S. S., Raju, S. S., Li, T., McCarthy, E., Chow, E., Aran, D., Ilano, A., Pai, C.-C. S., Rancan, C., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.017 · Cited by 734 · see citing works
TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision
Chen, Z., Ji, Z., Ngiow, S. F., Manne, S., Cai, Z., Huang, A. C., Johnson, J., Staupe, R. P., Bengsch, B., Xu, C., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.09.013 · Cited by 709 · see citing works
Cold and hot tumors: from molecular mechanisms to targeted therapy
Wu, B., Zhang, B., Li, B., Wu, H., & Jiang, M. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01979-x · Cited by 747 · see citing works
Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1-CD8+ Tumor-Infiltrating T Cells
Kurtulus, S., Madi, A., Escobar, G., Klapholz, M., Nyman, J., Christian, E., Pawlak, M., Dionne, D., Xia, J., Rozenblatt-Rosen, O., et al. (2019) · Immunity · doi:10.1016/j.immuni.2018.11.014 · Cited by 636 · see citing works
“T cells in the context of chronic viral infection and cancer (Brummelman et al., 2018; Leong et al., 2016; Philip et al., 2017; Utzschneider et al., 2016).”
InfluentialHudson, W. H., Gensheimer, J., Hashimoto, M., Wieland, A., Valanparambil, R. M., Li, P., Lin, J.-X., Konieczny, B. T., Im, S. J., Freeman, G. J., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.11.002 · Cited by 656 · see citing works
“…cell receptor (TCR) signaling but few described roles in CD8+ T cell exhaustion, such as Lax1, Cd101, and Pvrig, which encodes a recently-described inhibitory receptor for CD112 (Murter et al., 2019; Philip et al., 2017; Soares et al., 1998; Whelan et al., 2019; Zhu et al., 2002; Zhu et al., 2016).”
BackgroundInfluentialCD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions
Hashimoto, M., Kamphorst, A. O., Im, S. J., Kissick, H. T., Pillai, R. N., Ramalingam, S. S., Araki, K., & Ahmed, R. (2018) · Annual Review of Medicine · doi:10.1146/annurev-med-012017-043208 · Cited by 659 · see citing works
Fares, C. M., Allen, E. M. V., Drake, C. G., Allison, J. P., & Hu‐Lieskovan, S. (2019) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_240837 · Cited by 648 · see citing works
Cancer SLC43A2 alters T cell methionine metabolism and histone methylation
Bian, Y., Li, W., Kremer, D. M., Sajjakulnukit, P., Li, S., Crespo, J., Nwosu, Z. C., Zhang, L., Czerwonka, A., Pawłowska, A., et al. (2020) · Nature · doi:10.1038/s41586-020-2682-1 · Cited by 654 · see citing works
Targeting the epigenetic regulation of antitumour immunity
Hogg, S. J., Beavis, P. A., Dawson, M. A., & Johnstone, R. W. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0077-5 · Cited by 653 · see citing works
Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity
Binnewies, M., Mujal, A. M., Pollack, J. L., Combes, A. J., Hardison, E. A., Barry, K. C., Tsui, J. L., Ruhland, M. K., Kersten, K., Abushawish, M., et al. (2019) · Cell · doi:10.1016/j.cell.2019.02.005 · Cited by 629 · see citing works
“Indeed, given the apparent irreversibility of certain forms of exhaustion (Philip et al., 2017), it is possible that the efficacy of ICB is linked to ongoing de novo lymph node priming rather than only blockade of checkpoint ligands in the tumor.”
BackgroundInfluentialTransient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling
Weber, E. W., Parker, K. R., Sotillo, E., Lynn, R. C., Anbunathan, H., Lattin, J., Good, Z., Belk, J. A., Dániel, B., Klysz, D. D., et al. (2021) · Science · doi:10.1126/science.aba1786 · Cited by 625 · see citing works
“This hypothesis has been tested to a limited extent in murine models of chronic virus or cancer, whereby removal of antigen failed to reinvigorate exhausted T cells (9, 17, 50, 61).”
Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion
Yu, Y.-R., Imrichova, H., Wang, H., Chao, T., Xiao, Z., Gao, M., Rincon-Restrepo, M., Franco, F., Genolet, R., Cheng, W.-C., et al. (2020) · Nature Immunology · doi:10.1038/s41590-020-0793-3 · Cited by 593 · see citing works
The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies
Petitprez, F., Meylan, M., de Reyniès, A., Sautès‐Fridman, C., & Fridman, W. H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00784 · Cited by 602 · see citing works
“Interestingly, in mouse models, some dysfunctional CD8 T cells are nonetheless tumorspecific (92) and a subpopulation can be reactivated (92, 93).”
BackgroundVardhana, S. A., Hwee, M. A., Berisa, M., Wells, D. K., Yost, K. E., King, B., Smith, M., Herrera, P. S., Chang, H. Y., Satpathy, A. T., et al. (2020) · Nature Immunology · doi:10.1038/s41590-020-0725-2 · Cited by 575 · see citing works
Combination Cancer Therapy with Immune Checkpoint Blockade: Mechanisms and Strategies
Patel, S. A., & Minn, A. J. (2018) · Immunity · doi:10.1016/j.immuni.2018.03.007 · Cited by 574 · see citing works
“Similarly, DNMTi combined with a HDACi decreases exhaustion-associated genes expressed by TILs in a lung adenocarcinoma model (Topper et al., 2017).”
BackgroundInfluentialGenome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function
Shifrut, E., Carnevale, J., Tobin, V., Roth, T. L., Woo, J. M., Bui, C. T., Li, P. J., Diolaiti, M. E., Ashworth, A., & Marson, A. (2018) · Cell · doi:10.1016/j.cell.2018.10.024 · Cited by 573 · see citing works
T cell stemness and dysfunction in tumors are triggered by a common mechanism
Vodnala, S. K., Eil, R., Kishton, R. J., Sukumar, M., Yamamoto, T. N., Ha, N.-H., Lee, P.-H., Shin, M., Patel, S. J., Yu, Z., et al. (2019) · Science · doi:10.1126/science.aau0135 · Cited by 552 · see citing works
Epigenetic therapy in immune-oncology
Jones, P. A., Ohtani, H., Chakravarthy, A., & Carvalho, D. D. D. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0109-9 · Cited by 555 · see citing works
The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells
Mestermann, K., Giavridis, T., Weber, J., Rydzek, J., Frenz, S., Nerreter, T., Mades, A., Sadelain, M., Einsele, H., & Hudecek, M. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aau5907 · Cited by 531 · see citing works
Understanding subset diversity in T cell memory
Jameson, S. C., & Masopust, D. (2018) · Immunity · doi:10.1016/j.immuni.2018.02.010 · Cited by 523 · see citing works
“…while mouse and human memory CD8+ T cells have many gene expression characteristics in common with naïve T cells, recent studies reveal that the epigenetic landscape in memory CD8+ T cells shares many features with effector cells (Akondy et al., 2017; Philip et al., 2017; Youngblood et al., 2017).”
InfluentialEmerging Concepts for Immune Checkpoint Blockade-Based Combination Therapies
Zappasodi, R., Merghoub, T., & Wolchok, J. D. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.005 · Cited by 519 · see citing works
Self-citationEpigenetic control of CD8+ T cell differentiation
Henning, A. N., Roychoudhuri, R., & Restifo, N. P. (2018) · Nature reviews. Immunology · doi:10.1038/nri.2017.146 · Cited by 501 · see citing works
Man, K., Gabriel, S. S., Liao, Y., Gloury, R., Preston, S., Henstridge, D. C., Pellegrini, M., Zehn, D., Berberich‐Siebelt, F., Febbraio, M. A., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.11.021 · Cited by 489 · see citing works
CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment
Di Pilato, M., Kfuri-Rubens, R., Pruessmann, J. N., Ozga, A. J., Messemaker, M., Cadilha, B. L., Sivakumar, R., Cianciaruso, C., Warner, R. D., Marangoni, F., et al. (2021) · Cell · doi:10.1016/j.cell.2021.07.015 · Cited by 488 · see citing works
Precursor exhausted T cells: key to successful immunotherapy?
Kallies, A., Zehn, D., & Utzschneider, D. T. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0223-7 · Cited by 462 · see citing works
Metabolic and epigenetic regulation of T-cell exhaustion
Franco, F., Jaccard, A., Romero, P. J., Yu, Y.-R., & Ho, P. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00280-9 · Cited by 457 · see citing works
Beyond immune checkpoint blockade: emerging immunological strategies
Kubli, S. P., Berger, T., Araújo, D. V., Siu, L. L., & Mak, T. W. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00155-y · Cited by 460 · see citing works
CD8+ T cells in the cancer-immunity cycle
Giles, J. R., Globig, A.-M., Kaech, S. M., & Wherry, E. J. (2023) · Immunity · doi:10.1016/j.immuni.2023.09.005 · Cited by 467 · see citing works
PD-1 expression and clinical PD-1 blockade in B-cell lymphomas
Xu-Monette, Z. Y., Zhou, J., & Young, K. H. (2017) · Blood · doi:10.1182/blood-2017-07-740993 · Cited by 435 · see citing works
T‐cell exhaustion in HIV infection
Fenwick, C. W., Joo, V., Jacquier, P., Noto, A., Banga, R., Perreau, M., & Pantaleo, G. (2019) · Immunological Reviews · doi:10.1111/imr.12823 · Cited by 412 · see citing works
Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors
Melaiu, O., Lucarini, V., Cifaldi, L., & Fruci, D. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.03038 · Cited by 418 · see citing works
“Indeed, similarly to tumor-infiltrating T cells (103, 104), NK cells in the mouse lung cancer are functional during tumor initiation, while assume a mild dysfunctional state during tumor promotion that can be reverted by pharmacological FBP1 inhibition.”
BackgroundConnolly, K. A., Kuchroo, M. R., Venkat, A., Khatun, A., Wang, J., William, I., Hornick, N. I., Fitzgerald, B., Damo, M., Kasmani, M. Y., et al. (2021) · Science Immunology · doi:10.1126/sciimmunol.abg7836 · Cited by 403 · see citing works
Improving CAR-T immunotherapy: Overcoming the challenges of T cell exhaustion
Gumber, D., & Wang, L. D. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.103941 · Cited by 409 · see citing works
An NK-like CAR T cell transition in CAR T cell dysfunction
Good, C. R., Aznar, M. A., Kuramitsu, S., Samareh, P., Agarwal, S., Donahue, G., Ishiyama, K., Wellhausen, N., Rennels, A. K., Ma, Y., et al. (2021) · Cell · doi:10.1016/j.cell.2021.11.016 · Cited by 396 · see citing works
Mechanisms of Resistance to PD-1 and PD-L1 Blockade
Nowicki, T. S., Hu‐Lieskovan, S., & Ribas, A. (2018) · The Cancer Journal · doi:10.1097/ppo.0000000000000303 · Cited by 398 · see citing works
“While initially plastic and able to be modified to restore an effector functionality, they eventually reach a state of fixed epigenetic dysfunction, in which their chromatin is rendered inaccessible and resistant to further remodeling and reinvigoration.(86) The overall ratio of reinvigorated TEX to pretreatment tumor…”
Baessler, A., & Vignali, D. A. A. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-090222-110914 · Cited by 420 · see citing works
An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer
Voabil, P., de Bruijn, M., Roelofsen, L. M., Hendriks, S. H., Brokamp, S., van den Braber, M., Broeks, A., Sanders, J., Herzig, P., Zippelius, A., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01398-3 · Cited by 380 · see citing works
Cong, J., Wang, X., Zheng, X., Wang, D., Fu, B., Sun, R., Tian, Z., & Wei, H. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.06.021 · Cited by 376 · see citing works
Wei, S. C., Anang, N.-A. A. S., Sharma, R., Andrews, M. C., Reuben, A., Levine, J. H., Cogdill, A. P., Mancuso, J. J., Wargo, J. A., Pe’er, D., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1821218116 · Cited by 359 · see citing works
“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).”
BackgroundResultBelk, J. A., Yao, W., Ly, N., Freitas, K. A., Chen, Y.-T., Shi, Q., Valencia, A. M., Shifrut, E., Kale, N., Yost, K. E., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.06.001 · Cited by 382 · see citing works
“The enrichment of chromatin remodeling factors as hits in both in vitro and in vivo screens provides a complementary message to previous epigenomic profiling studies in T cell exhaustion (Pauken et al., 2016; Sen et al., 2016; Philip et al., 2017; ScottBrowne et al., 2016).”
BackgroundModulating Glycolysis to Improve Cancer Therapy
Chelakkot, C., Chelakkot, V. S., Shin, Y. K., & Song, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032606 · Cited by 378 · see citing works
Targeting TREM2 on tumor-associated macrophages enhances immunotherapy
Binnewies, M., Pollack, J. L., Rudolph, J., Dash, S., Abushawish, M., Lee, T., Jahchan, N. S., Canaday, P., Lu, E., Norng, M., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109844 · Cited by 365 · see citing works
Spatiotemporal Co-Dependency between Macrophages and Exhausted CD8 + T Cells in Cancer
Kersten, K., Hu, K. H., Combes, A. J., Samad, B., Harwin, T., Ray, A., Rao, A. A., Cai, E., Marchuk, K., Artichoker, J., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2022.05.004 · Cited by 348 · see citing works
Cancer Epigenetics, Tumor Immunity, and Immunotherapy
Cao, J., & Yan, Q. (2020) · Trends in Cancer · doi:10.1016/j.trecan.2020.02.003 · Cited by 298 · see citing works
“ATAC-seq showed that a consistent chromatin-remodeling program dominated the exhaustion of effector T cells, which was absent in the formation of memory T cells [72].”
BackgroundUnraveling the crosstalk between melanoma and immune cells in the tumor microenvironment
Marzagalli, M., Ebelt, N. D., & Manuel, E. R. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.08.002 · Cited by 345 · see citing works
“For example, in early dysfunction, T cells showed low expression of CD38, CD101, CD30L and high expression of CD5, while late dysfunction is characterized by the opposite pattern (102).”
BackgroundRotte, A., Jin, J., & Lemaire, V. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx686 · Cited by 346 · see citing works
Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity
Hutton, C., Heider, F., Blanco-Gomez, A., Banyard, A., Kononov, A., Zhang, X., Karim, S., Paulus-Hock, V., Watt, D., Steele, N., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.06.017 · Cited by 337 · see citing works
“T-3 (PD-1int CD39pos CD38neg GZMBpos CTLA-4pos 4-1BBpos T-BETpos) is phenotypically consistent with an active but not terminally exhausted phenotype and has been associated with improved capacity for expansion and tumor control (Leun et al., 2020; Philip et al., 2017).”
BackgroundPrinciples and therapeutic applications of adaptive immunity
Chi, H., Pepper, M., & Thomas, P. G. (2024) · Cell · doi:10.1016/j.cell.2024.03.037 · Cited by 359 · see citing works
Exhausted CD8+T Cells in the Tumor Immune Microenvironment: New Pathways to Therapy
Jiang, W., He, Y., He, W., Wu, G. S., Zhou, X., Sheng, Q., Zhong, W., Lu, Y., Ding, Y., Qi, L., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.622509 · Cited by 339 · see citing works
“In hot or altered-immunosuppressed tumors, the failure of immune monotherapy mainly results from TILs dysfunction, while ICB-based combination therapy mainly refers to improvement in T cell function (immune therapy targeting other co-inhibitory receptor such as CTLA-4, LAG-3, and Tim3) or the removal of inhibition fro…”
BackgroundInfluentialT Cell Dysfunction in Cancer Immunity and Immunotherapy
Xia, A., Zhang, Y., Jiang, X., Yin, T., & Lu, X. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01719 · Cited by 338 · see citing works
“On the other hand, the advanced state is fixed and cannot be changed by anti-PD-1 therapy (143).”
BackgroundTwo subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans
Galletti, G., De Simone, G., Mazza, E. M. C., Puccio, S., Mezzanotte, C., Bi, T. M., Davydov, A. N., Metsger, M., Scamardella, E., Alvisi, G., et al. (2020) · Nature Immunology · doi:10.1038/s41590-020-0791-5 · Cited by 299 · see citing works
Verma, V., Shrimali, R. K., Ahmad, S., Dai, W., Wang, H., Lu, S., Nandre, R., Gaur, P., Lopez, J., Sade-Feldman, M., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0441-y · Cited by 333 · see citing works
Self-citationSystemic dysfunction and plasticity of the immune macroenvironment in cancer models
Allen, B. M., Hiam-Galvez, K. J., Burnett, C. E., Venida, A. C., DeBarge, R., Tenvooren, I., Marquez, D. M., Cho, N. W., Carmi, Y., & Spitzer, M. H. (2020) · Nature Medicine · doi:10.1038/s41591-020-0892-6 · Cited by 328 · see citing works
Epigenetic regulation of T cell exhaustion
Belk, J. A., Dániel, B., & Satpathy, A. T. (2022) · Nature Immunology · doi:10.1038/s41590-022-01224-z · Cited by 333 · see citing works
Bengsch, B., Ohtani, T., Khan, O., Setty, M. N., Manne, S., O’Brien, S., Gherardini, P. F., Herati, R. S., Huang, A. C. C., Chang, K., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.04.026 · Cited by 319 · see citing works
“Recent epigenetic studies in mice and humans indicate that Tex cells represent a unique T cell lineage, compared to functional effector T (TEFF) cells and memory T (TMEM) cells (Pauken et al., 2016; Philip et al., 2017; Sen et al., 2016).”
BackgroundSingh, N., Lee, Y. G., Shestova, O., Ravikumar, P., Hayer, K. E., Hong, S. J., Lu, X. M., Pajarillo, R., Agarwal, S., Kuramitsu, S., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0813 · Cited by 295 · see citing works
“Together, these findings suggest that persistent exposure to leukemia leads to global programmatic changes in CART19 cells that are similar but not identical to classic, nonengineered T-cell exhaustion (15, 17, 21).”
BackgroundSelf-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells
Stanczak, M. A., Siddiqui, S. S., Trefny, M. P., Thommen, D. S., Boligan, K. F., von Gunten, S., Tzankov, A., Tietze, L., Lardinois, D., Heinzelmann-Schwarz, V. A., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120612 · Cited by 303 · see citing works
“A recent analysis of chromatin states in murine and human TILs from melanoma and NSCLC patients demonstrated a subpopulation within PD-1 hi TILs that had a relatively higher expression of CD5 and lower expression of CD38 and CD101 and that showed a greater potential for reprogrammability and reactivation (31).”
InfluentialPD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?
Xu-Monette, Z. Y., Zhang, M., Li, J., & Young, K. H. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01597 · Cited by 290 · see citing works
“However, the findings that PD-1hiCTLA-4hi TILs that were preferably expanded after anti-PD-1 therapy in melanoma patients (263) counters the findings in preclinical models [PD-1hi T cells were irreversible (178) and anti-PD-1 therapy was effective only in tumors with low frequencies of PD-1 + T cells (24)].”
BackgroundResultInfluentialSchenkel, J. M., Herbst, R. H., Canner, D. A., Li, A., Hillman, M., Shanahan, S.-L., Gibbons, G., Smith, O. C. G., Kim, J. Y., Westcott, P. M. K., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.08.026 · Cited by 287 · see citing works
Dong, L., Chen, C., Zhang, Y., Guo, P., Wang, Z., Li, J., Liu, Y., Liu, J., Chang, R., Li, Y., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.04.016 · Cited by 280 · see citing works
Epigenetic control of innate and adaptive immune memory
Lau, C. M., Adams, N. M., Geary, C. D., Weizman, O.-E., Rapp, M., Pritykin, Y., Leslie, C. S., & Sun, J. C.-Y. (2018) · Nature Immunology · doi:10.1038/s41590-018-0176-1 · Cited by 279 · see citing works
Self-citationZhang, M., Liu, C.-J., Tu, J., Tang, M., Ashrafizadeh, M., Nabavi, N., Sethi, G., Zhao, P., & Liu, S. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02305-x · Cited by 296 · see citing works
Giles, J. R., Ngiow, S. F., Manne, S., Baxter, A. E., Khan, O., Wang, P., Staupe, R., Abdel-Hakeem, M. S., Huang, H., Mathew, D., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01338-4 · Cited by 264 · see citing works
Peña-Romero, A. C., & Orenes‐Piñero, E. (2022) · Cancers · doi:10.3390/cancers14071681 · Cited by 261 · see citing works
Harnessing innate immune pathways for therapeutic advancement in cancer
Hu, A.-K., Sun, L., Lin, H., Liao, Y., Yang, H., & Mao, Y. Q. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01765-9 · Cited by 265 · see citing works
Self-citationAbdel-Hakeem, M. S., Manne, S., Beltra, J., Stelekati, E., Chen, Z., Nzingha, K., Ali, M.-A., Johnson, J. L., Giles, J. R., Mathew, D., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-00975-5 · Cited by 254 · see citing works
- 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 ›
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