Myeloid-derived suppressor cells coming of age

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a large array of pathologic conditions ranging from cancer to obesity. These cells represent a pathologic state of activation of monocytes and relatively immature neutrophils. MDSCs are characterized by a distinct set of genomic and biochemical features, and can, on the basis of recent findings, be distinguished by specific surface molecules. The salient feature of these cells is their ability to inhibit T cell function and thus contribute to the pathogenesis of various diseases. In this Review, we discuss the origin and nature of these cells; their distinctive features; and their biological roles in cancer, infectious diseases, autoimmunity, obesity and pregnancy.

Figure 1

Pathologic activation of neutrophils and monocytes. (a) In the presence of strong activation signals coming from pathogens in the form of toll-like receptors ligands (TLRL), damage associated molecular pattern (DAMP), pathogen-associated molecular patterns (PAMP) molecules monocytes and neutrophils are mobilized from the BM. This response results in classic myeloid cell activation. (b) In the presence of weak activation signal mediated mostly by growth factors and cytokines, myeloid cells undergo modest but continuous expansion. Pro-inflammatory cytokines and ER stress responses contribute to pathologic myeloid cells activation that manifests in weak phagocytic activity, increased production of reactive oxygen species (ROS), nitric oxide (NO), arginase 1 (not expressed in human monocytes and M-MDSC) and prostaglandin-E2 (PGE2). This results in immune suppression.

Figure 2

MDSC differentiation and accumulation. Neutrophils and monocytes are differentiated in bone marrow from hematopoietic progenitor cells (HPC) via common myeloid progenitors (CMP) and granulocyte-macrophage progenitors (GMP). Neutrophils differentiation progress through several progenitor and precursors stages. Among them are myeloblasts (MB), myelocytes (MC), metamyelocyte (MM), band forms (BF). Monocytes originate from monocyte/macrophages and dendritic cell (MDP) precursors. Under pathologic conditions, immature myeloid cells are expanded and converted to immunosuppressive MDSC. In early stages cells with some biochemical features of MDSC do not have suppressive activity and can be called MDSC-like cells. In cancer patients, in any given moment neutrophils and monocytes and pathologically activated MDSC co-exist, with accumulation of more MDSC during tumor progression. In tumors, M-MDSC rapidly differentiate in tumor associated macrophages (TAM) and inflammatory dendritic cells (infl DC).

Figure 3

MDSC role in obesity and pregnancy. (a) MDSC are expanded in obese subjects due to chronic inflammation and contribute to increase insulin sensitivity. MDSC in obese subjects directly inhibit T cells via NO secretion and induce macrophage differentiation to the M2 phenotype via IL-10 secretion, leading to increased susceptibility to infections. Moreover, increased MDSC increases cancer risk and favors metastatic spread of early stage cancers. (b) During pregnancy MDSC are expanded and are crucial for successful pregnancy. In pregnant women MDSC suppress T cells via ROS and Arg-1 thus sustaining maternal-fetal tolerance. Moreover, MDSC are expanded also in cord blood (CB) and neonates protecting newborns from infections and harmful inflammation.