Purpose: Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of pathologically expanded myeloid cells with immunosuppressive activity. In human disease, three major MDSC subpopulations can be defined as monocytic (M-MDSC), granulocytic [polymorphonuclear-MDSC (PMN-MDSC)], and early stage (e-MDSC), which lacks myeloid lineage markers of the former two subsets. The purpose of this study was to determine and compare the immunosuppressive capacity and clinical relevance of each of these subsets in patients with solid cancer.Experimental Design: The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in a cohort of 49 patients with advanced head and neck cancer (HNC) and 22 patients with urological cancers. Sorted and purified MDSC subsets were tested in vitro for their T-cell-suppressive capacity. Frequency of circulating MDSC was correlated with overall survival of patients with HNC.Results: A high frequency of PMN-MDSC most strongly correlated with poor overall survival in HNC. T-cell-suppressive activity was higher in PMN-MDSC compared with M-MDSC and e-MDSC. A subset of CD66b⁺/CD11b⁺/CD16⁺ mature PMN-MDSC displayed high expression and activity of arginase I, and was superior to the other subsets in suppressing proliferation and cytokine production of T cells in both cancer types. High levels of this CD11b⁺/CD16⁺ PMN-MDSC, but not other PMN-MDSC subsets, strongly correlated with adverse outcome in HNC.Conclusions: A subset of mature CD11b⁺/CD16⁺ PMN-MDSC was identified as the MDSC subset with the strongest immunosuppressive activity and the highest clinical relevance. Clin Cancer Res; 24(19); 4834-44. ©2018 AACR.

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