Cited by 271Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyAdenosine and Purinergic Signaling

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Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity

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Vignali, Paolo D. A., DePeaux, Kristin, Watson, McLane J., Ye, Chenxian, Ford, B. Rhodes, Lontos, Konstantinos, McGaa, Nicole K., Scharping, Nicole E., Menk, Ashley V., Robson, Simon C., Poholek, Amanda C., Rivadeneira, Dayana B., Delgoffe, Greg M.·2023·Nature Immunology

DOI 10.1038/s41590-022-01379-9PMC PMC10402660

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Abstract

CD8+ T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tT ex) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy. Here we show that intratumoral CD8+ tT ex cells possess transcriptional features of CD4+Foxp3+ regulatory T cells and are similarly capable of directly suppressing T cell proliferation ex vivo. tT ex cell suppression requires CD39, which generates immunosuppressive adenosine. Restricted deletion of CD39 in endogenous CD8+ T cells resulted in slowed tumor progression, improved immunotherapy responsiveness and enhanced infiltration of transferred tumor-specific T cells. CD39 is induced on tT ex cells by tumor hypoxia, thus mitigation of hypoxia limits tT ex suppression. Together, these data suggest tT ex cells are an important regulatory population in cancer and strategies to limit their generation, reprogram their immunosuppressive state or remove them from the TME might potentiate immunotherapy.

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Authors: Vignali, P. D. A., DePeaux, K., Watson, M. J., Ye, C., Ford, B. R., Lontos, K., McGaa, N. K., Scharping, N. E., Menk, A. V., Robson, S. C., Poholek, A. C., Rivadeneira, D. B., & Delgoffe, G. M.
Affiliations: University of Pittsburgh (US)
University of Pittsburgh Medical Center (US)
UPMC Hillman Cancer Center (US)
Beth Israel Deaconess Medical Center (US)
Corresponding author: Delgoffe, Greg M.
ORCID: Vignali, Paolo D. A.
DePeaux, Kristin
Watson, McLane J.
Ye, Chenxian
Ford, B. Rhodes
Lontos, Konstantinos
Scharping, Nicole E.
Menk, Ashley V.
Robson, Simon C.
Poholek, Amanda C.
Rivadeneira, Dayana B.
Delgoffe, Greg M.
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2022-12-21
Volume: 24
Issue: 2
Pages: 267-279
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/s41590-022-01379-9
PMC: PMC10402660
OpenAlex: W4312095486
Cited by: 269
References: 52
Citations by year: 2026: 49 · 2025: 86 · 2024: 85 · 2023: 49
FWCI: 23.21
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Cancer Research Institute
Alliance for Cancer Gene Therapy
University of Pittsburgh (T32CA082084, P30 CA047904)
National Institutes of Health (SU2C-AACR-IRG-04-16)
Stand Up To Cancer (SU2C-AACR-IRG-04-16)
Center for Research Computing, University of Pittsburgh
National Cancer Institute (F99CA222711, F31CA247129, P50CA121973, F30CA247034, K00CA222711, T32CA082084, P50CA097190, P30CA047904, R01CA277473)
National Institute of General Medical Sciences (T32GM008208)
National Institute of Allergy and Infectious Diseases (F31AI149971, DP2AI136598, R01AI171483, R01AI166598)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Keywords: CD39, tumor hypoxia, exhausted T cells, CD8+ T cells, regulatory T cells, Foxp3, adenosine, immunosuppression, tumor microenvironment, immunotherapy resistance, checkpoint blockade, tumor progression, T cell proliferation inhibition
MeSH terms: Hypoxia, Apyrase, Humans, Neoplasms, Antigens, CD, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Tumor Microenvironment

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Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity

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