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Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity
Open accessAbstract
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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“Independent of glycolysis, the HIFs can induce the production of immunosuppressive metabolites such as adenosine by transcriptionally activating ectoenzymes such as ENTPD2/CD39L1, CD39, and CD73 (Table 1), which contribute to the multistep conversion of extracellular ATP through ADP/AMP to adenosine, thus promoting the maintenance of MDSCs, which limits the activity of immune checkpoint inhibitors”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [92]
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Metadata
- 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
- Venue
- Nature Immunology
- Published
- 2022-12-21
- Volume
- 24
- Issue
- 2
- Pages
- 267-279
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- 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
- 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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