The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade
Open accessAbstract
T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8+ tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8+ TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8+ TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8+ T cells might be an important component of improving the response to checkpoint blockade.
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“Conversely, terminal Tex (Ttex) cells accumulate over time and respond poorly to ICB therapies8,11–13.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [11]
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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Spatial reconstruction of single-cell gene expression data
Satija, R., Farrell, J. A., Gennert, D., Schier, A. F., & Regev, A. (2015) · Nature Biotechnology · doi:10.1038/nbt.3192 · Cited by 7,055
PD-1 blockade induces responses by inhibiting adaptive immune resistance
Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J. M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., et al. (2014) · Nature · doi:10.1038/nature13954 · Cited by 6,609
Buenrostro, 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
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
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062
Restoring function in exhausted CD8 T cells during chronic viral infection
Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., Freeman, G. J., & Ahmed, R. (2005) · Nature · doi:10.1038/nature04444 · Cited by 4,057
Self-citationControl of Viremia in Simian Immunodeficiency Virus Infection by CD8 + Lymphocytes
Schmitz, J. E., Kuroda, M. J., Santra, S., Sasseville, V. G., Simon, M. A., Lifton, M. A., Rácz, P., Tenner‐Racz, K., Dalesandro, M. R., Scallon, B. J., et al. (1999) · Science · doi:10.1126/science.283.5403.857 · Cited by 2,167
Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103
Self-citationTargeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K., & Anderson, A. C. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100643 · Cited by 2,072
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Self-citationCD8+ T cell states in human cancer: insights from single-cell analysis
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Metadata
- Authors
- Miller, 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., Manos, M., Gjini, E., Kuchroo, J. R., Ishizuka, J. J., Collier, J. L., Griffin, G. K., Maleri, S., Comstock, D. E., Weiss, S. A., Brown, F. D., Panda, A., Zimmer, M. D., Manguso, R. T., Hodi, F. S., Rodig, S. J., Sharpe, A. H., & Haining, W. N.
- Affiliations
- Broad Institute (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Haining, W. Nicholas
- ORCID
- Miller, Brian C.
- Sen, Debattama R.
- Al Abosy, Rose
- Bi, Kevin
- Virkud, Yamini V.
- LaFleur, Martin W.
- Yates, Kathleen B.
- Lako, Ana
- Felt, Kristen
- Naik, Girish S.
- Manos, Michael
- Gjini, Evisa
- Kuchroo, Juhi R.
- Ishizuka, Jeffrey J.
- Collier, Jenna L.
- Griffin, Gabriel K.
- Comstock, Dawn E.
- Weiss, Sarah A.
- Zimmer, Margaret D.
- Manguso, Robert T.
- Hodi, F. Stephen
- Rodig, Scott J.
- Sharpe, Arlene H.
- Haining, W. Nicholas
- Venue
- Nature Immunology
- Published
- 2019-02-18
- Volume
- 20
- Issue
- 3
- Pages
- 326-336
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC6673650
- OpenAlex
- W2913558101
- Cited by
- 2,087
- References
- 53
- Citations by year
- 2026: 319 · 2025: 334 · 2024: 358 · 2023: 300 · 2022: 276 · 2021: 269 · 2020: 176 · 2019: 55
- FWCI
- 81.19
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-10-03)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (KL2TR002542)
- National Heart, Lung, and Blood Institute (T32HL007627)
- National Cancer Institute (T32CA207021, T32CA009172)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Allergy and Infectious Diseases (R01AI115712, K23AI130408, U19AI133524, P01AI056299)
- National Center for Advancing Translational Sciences
- 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 exhaustion, CD8+ T cells, PD-1, anti-PD-1 therapy, immune checkpoint blockade, tumor-infiltrating lymphocytes, melanoma, T cell polyfunctionality, chronic viral infection, tumor control
- MeSH terms
- Animals, Female, Humans, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Melanoma, Experimental, Mice, Inbred C57BL, Lymphocyte Subsets, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Antibodies, Blocking, Mice, Congenic, Cell Line, Tumor, Programmed Cell Death 1 Receptor
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