The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment

Abstract

Myeloid-derived suppressor cells (MDSC) are one of the major components of the tumor microenvironment. The main feature of these cells is their potent immune suppressive activity. MDSC are generated in the bone marrow and, in tumor-bearing hosts, migrate to peripheral lymphoid organs and the tumor to contribute to the formation of the tumor microenvironment. Recent findings have revealed differences in the function and fate of MDSC in the tumor and peripheral lymphoid organs. We review these findings here and, in this context, we discuss the current understanding as to the nature of these differences, the underlying mechanisms, and their potential impact on the regulation of tumor progression.

Figure 1. MDSC function in tumor site and peripheral lymphoid organs

In peripheral lymphoid organs, immune suppression by MDSC is mainly antigen-specific, contact-dependent and utilizes several major pathways, including the production of reactive nitrogen and oxygen species (NO, ROS and PNT), elimination of key nutrition factors for T cells from the microenvironment (L-arginine, L-tryptophan and L-cysteine), disruption of homing of T cells (through the expression of ADAM17), production of immunosuppressive cytokines (TGF-β, IL-10), and induction of T regulatory (Treg) cells. After migration to the tumor, MDSC are exposed to inflammatory and hypoxic tumor microenvironment. This results in significant HIF-1α-mediated elevation of Arg1 and iNOS and downregulation of ROS production, upregulation of inhibitory PD-L1 on MDSC surface, and production of CCL4 and CCL5 chemokines attracting Tregs to the tumor. Overall, these alterations result in more potent non-specific immunosuppressive activity of MDSCs inside the tumor.

Figure 2. Mechanism of M-MDSC differentiation to tumors and peripheral lymphoid organs

Mon/M-MDSC are produced in the BM from hematopoietic progenitor cells and recruited to the tumor by several chemokines (described in more details in Table 1). Hypoxic conditions, including HIF1α, prevalent in the TME induces the downregulation of pSTAT3, which results in M-MDSC differentiation to TAM. Other factors known to induce TAM differentiation are activation of CD45 phosphatase, LIF, IL-6, and thrombin. In the spleen, Mon/M-MDSC have a high level of pSTAT3 due to the lack of hypoxic conditions. High STAT3 activity prevents differentiation of Mon/M-MDSC to TAM in the spleen.

Figure 3. The effect of the tumor microenvironment on the metabolism of myeloid cells

Lactic acid produced by tumor cells and IL-4 produced by Th2 cells in the TME can drive the metabolism of TAM and TADC towards oxidative phosphorylation (oxphos) while inhibiting glycolysis. Lipids are known to have a role in negative regulation of TADC function. MDSC in peripheral tissue have decreased rates of oxphos and glycolysis compared to tumor-infiltrating MDSC (T-MDSC). Fatty acids derived from the TME drive the metabolism of T-MDSC towards fatty acid oxidation (FAO) and oxphos. Glycolytic rates are also increased in T-MDSC but how the TME influences this process, and the role AMPK plays in this process is unclear.