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CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-?-mTOR-HIF-1 signaling in patients with non-small cell lung cancer.

ABSTRACT: 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-? 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-? triggered phosphorylation of mammalian target of rapamycin, and subsequently activated hypoxia-inducible factor-1? (HIF-1?) 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.

SUBMITTER: Li J

PROVIDER: S-EPMC5486179 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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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.

Li Jieyao J Wang Liping L Chen Xinfeng X Li Lifeng L Li Yu Y Ping Yu Y Huang Lan L Yue Dongli D Zhang Zhen Z Wang Fei F Li Feng F Yang Li L Huang Jianmin J Yang Shuangning S Li Hong H Zhao Xuan X Dong Wenjie W Yan Yan Y Zhao Song S Huang Bo B Zhang Bin B Zhang Yi Y

Oncoimmunology 20170421 6

CD39/CD73-adenosine pathway has been recently defined as an important tumor-induced immunosuppressive mechanism. We here documented a fraction of CD11b<sup>+</sup>CD33<sup>+</sup> 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 ...[more]

PMID: 28680754

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Project description:BackgroundEcto-5'-nucleotidase (cluster of differentiation 73/CD73) is an ectonucleotidase that is being evaluated as a biomarker for the diagnosis and prognosis of various types of cancer. However, the clinicopathological relationship between CD73 expression in monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSC (PMN-MDSCs) in head and neck squamous cell carcinomas (HNSCCs) is not clear. Understanding the phenotypic and functional characteristics of human CD73+ MDSCs in the tumor microenvironment could help elucidate the roles of these cells in the ontogeny, spread, and treatment of solid cancer.MethodsIn the present study, we first analyzed the expression percentage of human M-MDSCs and PMN-MDSCs subsets circulating in peripheral blood of patients with head and neck tumors originated in nasopharynx, oropharynx, oropharynx and larynx. To identify the correlation between phenotypic characteristics of MDSCs and clinical stages in HNSCC, we extended the study by analyzing the percentage, CD73 phenotype and immunosuppressive function of MDSCs and the correlation with the clinical parameters. Moreover, we compare the functions of both M-MDSCs and PMN-MDSCs blunts T-cell function in an ectonucleotidase-dependent manner.ResultsOur study revealed that PMN-MDSCs were significantly increased in HNSCC patients, contributing to MDSC-mediated T cell immune suppression. Our results indicated that PMN-MDSCs comprised the majority of MDSCs participating in anticancer immunosuppression. The increase in PMN-MDSCs was directly correlated with the clinical stages of HNSCC. Levels of CD73 were increased in PMN-MDSCs and were correlated with the clinical stages of HNSCC. The ectonucleotidase inhibitor adenosine 5'-(α,β-methylene)diphosphate (APCP) decreased its suppression towards T cell proliferation. Ectonucleotidase inhibitors are promising candidates for the treatment of HNSCC.ConclusionsThese studies demonstrate the expansion of PMN-MDSCs correlated with expression of CD73 and increasing clinical stages in HNSCC. These CD73+ PMN-MDSCs contributes to T cell immune suppression activity in HNSCC patients. Using ectonucleotidase inhibitors is a promising rationale for PMN-MDSCs in future clinical development of immunotherapy in human HNSCC cancer.

Dataset Information

CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-?-mTOR-HIF-1 signaling in patients with non-small cell lung cancer.

Publications

CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-β-mTOR-HIF-1 signaling in patients with non-small cell lung cancer.

Similar Datasets

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