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CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-β-mTOR-HIF-1 signaling in patients with non-small cell lung cancer
Open accessAbstract
CD39/CD73-adenosine pathway has been recently defined as an important tumor-induced immunosuppressive mechanism. We here documented a fraction of CD11b+CD33+ myeloid-derived suppressor cells (MDSCs) in peripheral blood and tumor tissues from non-small cell lung cancer (NSCLC) patients expressed surface ectonucleotidases CD39 and CD73. Tumor TGF-β stimulated CD39 and CD73 expression, thereby inhibited T cell and NK cell activity, and protected tumor cells from the cytotoxic effect of chemotherapy through ectonucleotidase activity. Mechanistically, TGF-β triggered phosphorylation of mammalian target of rapamycin, and subsequently activated hypoxia-inducible factor-1α (HIF-1α) that induced CD39/CD73 expression on MDSCs. CD39 and CD73 on MDSCs, therefore, link their immunosuppressive and chemo-protective effects to NSCLC progression, providing novel targets for chemo-immunotherapeutic intervention.
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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 [91]
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Metadata
- Authors
- Li, J., Wang, L., Chen, X., Li, L., Li, Y., Ping, Y., Huang, L., Yue, D., Zhang, Z., Wang, F., Li, F., Yang, L., Huang, J., Yang, S., Li, H., Zhao, X., Dong, W., Yan, Y., Zhao, S., Huang, B., Zhang, B., & Zhang, Y.
- Affiliations
- First Affiliated Hospital of Zhengzhou University (CN)
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Northwestern University (US)
- Corresponding author
- Wang, Liping
- Zhang, Bin
- Zhang, Yi
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2017-05-30
- Volume
- 6
- Issue
- 6
- Pages
- e1320011-e1320011
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC5486179
- OpenAlex
- W2605835842
- Cited by
- 299
- References
- 57
- Citations by year
- 2026: 22 · 2025: 32 · 2024: 33 · 2023: 33 · 2022: 52 · 2021: 45 · 2020: 37 · 2019: 26 · 2018: 19
- FWCI
- 17.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- OncoImmunology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81171985, 112300410153, 122300410155, 81171986, 20110110001)
- Science and Technology Department of Henan Province
- National Institutes of Health (CA149669)
- National Cancer Institute (R01CA208354)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- CD39/CD73, myeloid-derived suppressor cells, non-small cell lung cancer, TGF-beta, mTOR, HIF-1α, adenosine pathway, ectonucleotidases, tumor immunosuppression, chemoresistance, T cell suppression, NK cell inhibition, chemoimmunotherapy
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