CD73 expression in myeloid-derived suppressor cells is correlated with clinical stages in head and neck squamous cell carcinomas

Abstract

Background: Ecto-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. Methods: In 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. Results: Our 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. Conclusions: These 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.

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“…Approximately half a million patients are diagnosed annually with HNSC, and it is a major contributor to cancerrelated mortality worldwide [2]. The pathogenesis of HNSC is multifactorial [3,4], including (a) an acute demand for protein synthesis that is often a result of oncogene activation, (b) inadequate oxygen and nutrient supply as well as chemo/radiotherapy exposure, and (c) immune surveillance escape [5][6][7].…”

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“…In the tumor state, MDSCs are abnormally produced and recruited to the TME to help establish an immunosuppressive TME and promote tumor angiogenesis and metastasis to support tumor progression. There are two main types of MDSCs, mononuclear MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) (134). In tumors, M-MDSC can quickly differentiate into TAMs (135,136), and the relationship between TAMs and ECs and the promotion of tumors have been discussed above.…”

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“…30 Data from both in vitro and in vivo studies suggest the presence of MDSC markers that correlate with cancer conditions in humans. 31,32 Translational studies have also demonstrated the predictive value of MDSCs in esophageal squamous cell carcinoma (ESCC) patients. 33 However, there is a shortage of published clinical data on MDSC-targeted cancer therapy due to the lack of novel MDSC targets.…”