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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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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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