Plasticity of myeloid-derived suppressor cells in cancer

Abstract

In recent years, myeloid-derived suppressor cells (MDSC) have emerged as one of the major inhibitors of immune effector cell function in cancer. MDSC represent a heterogeneous population of largely immature myeloid cells that are characterized by a pathological state of activation and display potent immune suppressive activity. Two major subsets of MDSC have been identified: monocytic (M-MDSC) and polymorphonuclear (PMN-MDSC). PMN-MSDC share phenotypic and morphologic features with neutrophils, whereas M-MDSC are similar to monocytes and are characterized by high plasticity. Differentiation of M-MDSC to macrophages and dendritic cells is shaped by tumor microenvironment. In recent years, the mechanisms of this process start to emerge.

Figure 1. Origin of MDSC

MDSC differentiate from common myeloid progenitors (CMP), and follow the pathway that involves granulocyte-macrophage progenitor (not shown) and various intermediate progenitors and precursors including common monocyte progenitors (cMOP). Figure shows most common changes observed in MDSC as compared to monocytes and neutrophils.

Figure 2. Differentiation of M-MDSC in tissues

M-MDSCs are generated in bone marrow and migrate to tumor site attracted by chemokines (CCL2, CCL5) and growth factor CSF1. They differentiate to tumor associated macrophages (TAM) and inflammatory dendritic cells (DC). This process is controlled by a number of transcription factors (depicted in the figure). Among them HIF-1α is one of the most well studied. Hypoxia triggers down-regulation of STAT3 and promotes M-MDSC differentiation to TAM. Although TAM polarization towards M1 and M2 has been described in many conditions, clear dissociation between these states is difficult. Importantly, it appears that both populations can inhibit T-cell function using different mechanisms (NO for M1 and arginase1 for M2 TAM). The functional outcomes depend on the conditions of tumor microenvironment.