Figure 2.

Multiple immunosuppressive mechanisms of MDSCs on NK, DCs, Th17, Tregs. MDSCs directly inhibit autologous natural killer (NK) cell cytotoxicity and cytokine secretion by interaction with the NKp30 on NK cells. Also, MDSCs indirectly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity (ADCC), cytokine production, and signal transduction through the production of NO, TGFβ, and H2O2. Immature NK cells can be converted into MDSCs by tumor-derived GM-CSF. MDSCs activate NK cells to produce high amounts of IFN‐γ, which depends partially on the interaction of NKG2D on NK cells with NKG2D ligand RAE-1 on MDSCs and the IFNAR pathway. MDSCs inhibited IL-12 production of DCs by IL-10 and suppressed T-cell stimulatory activity of DCs. Myeloperoxidase (MPO)-driven lipid peroxidation in PMN-MDSCs blocked cross-presentation by DCs. Arg1-dependent production of polyamines by MDSCs conditioned DCs toward an immunosuppressive phenotype via activation of the Src kinase. S100A8 and S100A9 produced by MDSCs inhibited DCs differentiation from hematopoietic progenitor cells (HPCs) via persistent upregulation of ROS. MDSCs secrete Th17-driving cytokines (IL-1β, IL-6, and IL-23) and produce NO and Prostaglandin-E2 (PGE2) to facilitate Th17 cells differentiation; the latter required nitric oxide synthase (NOS) and cyclooxygenase 2 (COX-2) activity. Additionally, MDSCs promote the recruitment of Th17 cells through CCL4 and induce secretion of IL-17 by CD4(+) T cells through secretion of IL-1β. MDSCs induce Foxp3+ Tregs from naive CD4+ T cells and monocyte-induced Th17 cells via MDSCs-derived TGF-β and retinoic acid. PGE2 produced by MDSCs expand IL-10-producing Treg subsets.