Figure 1.

Immunosuppressive mechanisms and cell targets of MDSCs. T cells are the primary target of MDSCs. MDSCs produce a high level of nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (PNT), which suppress T cells by inhibiting proliferation, inducing apoptosis, decreasing the TCR ζ-chain and nitrating the TCR complex. MDSCs deplete amino acids essential for T-cell response. For instance, MDSCs decrease L-arginine and tryptophan level through arginase 1 (ARG1) and indoleamine 2, 3-dioxygenase (IDO), respectively, and reduce the cysteine availability through cystine uptake. CD39/CD73 expression by MDSCs produces adenosine that inhibits T cells through adenosine receptors. By shedding CD62L (L-selectin) off the T-cell surface or by nitrating CCL2, MDSCs interrupt T-cell trafficking to the periphery or tumor site. MDSCs express both programmed cell death-ligand 1 (PD-L1), which inhibits T cells through interaction with programmed cell death protein 1 (PD-1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), whose precise role remains unclear. IL-10 and TGF-β, two major immunosuppressive cytokines produced by MDSCs, are implicated in T-cell suppression and regulatory T cell (Treg) induction. MDSCs also induce Tregs through CD40 in a contact-dependent manner and recruit Tregs through the production of various chemokines. In addition to T cells, MDSCs suppress natural killer (NK) cells and dendritic cells (DCs), inhibit B cells, and induce regulatory B cells (Bregs). Lastly, tumor-infiltrating MDSCs, mostly M-MDSCs, may differentiate into suppressive DCs and tumor-associated macrophages (TAMs). ADAM17, a disintegrin and metalloproteinase 17; iNOS, inducible nitric oxide synthase; NOX2, NADPH oxidase 2.