Myeloid-derived suppressor cells in transplantation and cancer

Abstract

Myeloid-derived suppressor cells (MDSC) are myeloid cells that suppress the immune response, a definition that reflects both their origin and their function. As negative regulators of the immune response, MDSC represent a novel therapeutic approach for manipulating the immune system toward tolerance or immunity. MDSC are present in cancer patients and tumor-bearing mice and are in part responsible for the inhibition of the cell-mediated immune response against the tumor. Our laboratories investigate the immunologic mechanisms of tumor acceptance mediated by MDSC, which can be exploited to prevent allograft rejection in transplantation. A better understanding of MDSC biology will open new avenues for therapeutic intervention, either by inhibiting their function (i.e. in cancer patients), or by enhancing their suppressive effects and promoting their expansion (i.e. in organ transplantation and alloimmune responses). In this review, we summarize some of the critical aspects of the immunoregulatory function of MDSC in cancer and transplantation and discuss their potential clinical applications.

Fig. 1

MDSC subsets. Cytospin preparations of CD11b-expressing Ly6C^hi Ly6G⁻, Ly6C^int Ly6G⁻, Ly-6C^lo Ly6G⁻, and Ly6C^int Ly6G⁺ myeloid cells from tolerant allografts

Fig. 2

Suppressive mechanisms of MDSC. a MDSC-mediated T-cell suppression. IFN-gamma signaling mediates the induction of tolerance mediated by MDSC through activating STAT-1-dependent pathways, including iNOS activation and ROS production. b MDSC-mediated Treg development. IFN-gamma signaling mediates the induction of tolerance mediated by MDSC through activating STAT-1-dependent pathways, including PDL-1 expression and IL-10 plus TGF-β secretion

Fig. 3

M-MDSC activation and differentiation in tumor microenvironment. M-MDSC can differentiate into M1-like phenotype (controlled by TLR ligands, C5a, INFγ, IL-12, and IL-1β), which have antitumor effect through the production of iNOS. Alternatively, M-MDSC can differentiate into M2-like phenotype (controlled by IL-10, IL-6, TGF-β, IL-13, and IL-4), which promotes tumor growth, tissue remodeling and angiogenesis through producing IL-10 and arginase. In addition, the expansion of MDSC population can be controlled by VEGF, GM-CSF, G-CSF, M-CSF, SCF1, prostaglandins, S100A8/A9, and FLT3