Individuals with advanced cancer are frequently immunosuppressed,

Individuals with advanced cancer are frequently immunosuppressed, lack effective innate and adaptive

antitumor immunity, and are poorly responsive to active immunotherapy. Assorted tumor-secreted factors drive the accumulation of multiple immune suppressive mechanisms [1]. Tumor-secreted factors act directly to activate suppressive mechanisms, or indirectly by inducing host cells that reduce immunocompetence [2]. Different cancers stimulate diverse inhibitory mechanisms; however, myeloid-derived suppressor cells (MDSCs) are induced by virtually all cancers and are an obstacle to antitumor immunity [3]. Mouse MDSCs are a heterogeneous cell population consisting of CD11b+Gr1+ cells. Two major subpopulations are defined based on the differential expression of Ly6C and Ly6G, the components of Gr1. Monocytic MDSCs (MO-MDSCs) BAY 73-4506 ic50 are mononuclear and CD11b+Ly6G−Ly6Chi, while granulocytic MDSCs (PMN-MDSCs, where PMN-MDSCs are defined as polymorphonuclear MDSCs) are polymorphonuclear and CD11b+Ly6G+Ly6Clow/− [4, 5]. Gr1 levels roughly correlate with Ly6G levels, so that CD11b+Gr1hi/med cells tend to be CD11b+Ly6G+Ly6C−/low PMN-MDSCs [6]. Both subpopulations this website suppress by the production of arginase, while MO-MDSCs also produce nitric oxide (NO) [4, 5]. Although not as well characterized, comparable subpopulations exist in cancer patients [7-9]. Various tumor-produced

factors, including granulocyte-macrophage-colony stimulating factor (GM-CSF) [6, 8, 10-13], IL-1β [14, 15], IL-6 [16], cyclooxygenase-2 and prostaglandin E2 [17, 18], S100A8/A9 [19, 20], and vascular endothelial growth factor [21] facilitate MDSC development and/or suppressive activity. Because MDSCs are induced by any one of these factors, no single molecule is essential for generating MDSCs. In contrast, IFN-γ [10, 22] and IL-4 receptor alpha (IL-4Rα) [9, 23] have been reported as

essential for MDSC development and/or suppressive activity. Two of these studies used MDSC “cell lines” [22, 23], so the applicability of the results to primary MDSCs is unclear. The requirement for IFN-γ [4] and IL-4Rα Calpain [9, 16] has been attributed to the development and suppressive activity of MO-MDSCs and PMN-MDSCs, respectively. IL-4Rα is also considered a marker for human MDSCs [9]. However, other studies demonstrated that IL-4Rα [5, 24] and IFN-γ [25] are not essential for murine MDSC accumulation or suppression. If IFN-γ and/or IL-4Rα are critical for MDSC development and function, then manipulation of these molecules could impact MDSC-mediated immune suppression. Therefore, it is important to clarify the role of IFN-γ and IL-4Rα in MDSC biology. Given the inconsistencies in the literature, we evaluated the role of these molecules using IFN-γ-deficient, IFN-γR-deficient (where IFN-γR is defined as interferon gamma receptor), and IL-4Rα-deficient mice using three C57BL/6-derived and three BALB/c-derived tumors that induce monocytic and granulocytic MDSCs.

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