Mechanism of Myeloid-Derived Suppressor Cell Differentiation in Cancer.

Abstract SCI-31

Myeloid-derived suppressor cells (MDSC) represent an intrinsic part of myeloid cell lineage and comprised of myeloid progenitors and precursors of myeloid cells. In healthy host upon generation in bone marrow immature myeloid cells (IMC) quickly differentiate into mature granulocytes, macrophages, or dendritic cells. In a number of pathological conditions (cancer, various infections diseases, sepsis, trauma, bone marrow transplantation, autoimmune abnormalities) increased production of IMC is associated with partial block of their differentiation and most importantly pathological activation of these cells manifests in up-regulation of arginase, inducible nitric oxide synthase (iNOS) and NO production, increased level of reactive oxygen species (ROS). This results in expansion of IMC with immune suppressive activity. Accumulation of MDSC was detected in practically all mouse tumor models and in patients with different types of cancer. In mice, MDSCs are characterized by the co-expression of myeloid lineage differentiation antigen Gr1 and CD11b. In humans, MDSC are currently defined as CD14^-CD11b⁺ cells or more narrowly as cells that express the common myeloid marker CD33 but lack the expression of markers of mature myeloid and lymphoid cells and the MHC class II molecule HLA-DR. Recently, the morphological heterogeneity of these cells in mice was defined more precisely based on the expression of cell-surface markers Ly6G and Ly6C. Granulocytic MDSCs have a CD11b⁺Ly6G⁺Ly6C^low phenotype, whereas MDSCs with monocytic morphology are CD11b⁺Ly6G^-Ly6C^high. These two subpopulations may have different functions. Accumulation of MDSC is caused by different soluble factors. Recent studies have demonstrated that factors implicated in regulating the expansion of MDSCs can be provisionally split into two main groups with partially overlapping activity. The first group includes factors that are produced primarily by tumor cells and promote the expansion of MDSC through myelopoiesis stimulation, which is associated with inhibition of myeloid-cell differentiation. These factors include stem-cell factor (SCF), macrophage colony-stimulating factor (M-CSF), IL-6, granulocyte/macrophage colony-stimulating factor (GM-CSF) and vascular endothelial growth factor (VEGF) and others. Signalling pathways triggered by most of these factors in MDSCs converge on signal transducer and activator of transcription 3 (STAT3). One of the potential targets for STAT3 was recently identified as S100A8/A9 proteins. Accumulation of these proteins in myeloid progenitors prevents their differentiation and results in expansion of MDSC. The second group of factors are produced primarily by activated T cells and tumor stroma and directly activate MDSC. These factors, which include IFN gamma, IL-13, IL-4 and TGFβ, among others, activate several different signaling pathways in MDSCs that involve STAT6, STAT1, and NF-kB. Most studies have shown that the immune-suppressive function of MDSCs requires direct cell–cell contact, which indicates that they operate either through cell-surface receptors and/or through the release of short-lived soluble mediators. Currently, a number of clinical trials explores the possibility of regulating immune responses in cancer by depleting ot inactivating MDSC in cancer patients.