Cited by 2,087Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade

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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., Maleri, Seth, Comstock, Dawn E., Weiss, Sarah A., Brown, Flavian D., Panda, Arpit, Zimmer, Margaret D., Manguso, Robert T., Hodi, F. Stephen, Rodig, Scott J., Sharpe, Arlene H., Haining, W. Nicholas·2019·Nature Immunology

DOI 10.1038/s41590-019-0312-6PMC PMC6673650

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Abstract

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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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
Publisher: Springer Science and Business Media LLC
Published: 2019-02-18
Volume: 20
Issue: 3
Pages: 326-336
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/s41590-019-0312-6
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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Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade

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