Myeloid-derived suppressor cells as regulators of the immune system

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

Figure 1. The origin of MDSCs

Immature myeloid cells (IMCs) are part of the normal process of myelopoiesis, which takes place in the bone marrow and is controlled by a complex network of soluble factors that include cytokines such as granulocyte/macrophage colony-stimulating factor (GM-CSF), stem-cell factor (SCF), interleukin-3 (IL-3), FMS-related tyrosine kinase 3 (FLT-3), macrophage colony-stimulating factor (M-CSF) and cell-expressed molecules including Notch (not shown). Haematopoietic stem cells (HSCs) differentiate into common myeloid progenitor (CMP) cells and then into IMCs. Normally, IMCs migrate to different peripheral organs, where they differentiate into dendritic cells, macrophages and/or granulocytes. However, factors produced in the tumour microenvironment and/or during acute or chronic infections, trauma or sepsis, promote the accumulation of IMCs at these sites, prevent their differentiation and induce their activation. These cells exhibit immunosuppressive functions and are therefore known as myeloid-derived suppressor cells (MDSCs). MDSCs can also differentiate into tumor-associated macrophages (TAMs) within the tumour environment, which are cells that have a phenotype and function that is distinct from MDSCs.

Figure 2. Signalling pathways involved in the expansion of MDSC populations

The accumulation of myeloid-derived suppressor cells (MDSCs) is regulated by several factors that are released by tumour cells, tumour stromal cells, activated T cells and macrophages, apoptotic tumour cells, bacterial and viral agents and by pathogen-infected cells. These factors trigger several different signalling pathways in MDSCs that mainly involve the STAT (signal transducer and activator of transcription) family of transcription factors. STAT3 regulates the expansion of MDSCs by stimulating myelopoiesis and inhibiting myeloid-cell differentiation. It also contributes to the increased production of reactive oxygen species (ROS) by MDSCs. The activation of STAT6 and STAT1, as well as TLR-mediated activation of nuclear factor-κB (NF-κB), by these factors results in the activation of MDSCs, which leads to the upregulation of iNOS and arginase and increased production of suppressive cytokines such as transforming growth factor-β (TGF-β). In combination with STAT3 they also contribute to upregulation of ROS production by these cells. S100A8 and S100A9 directly bind to p67phox and p47phox, which are crucial components of NADPH complex. This binding potentiates NADPH oxidase activation in MDSCs, which causes increased production of ROS, leading to the observed suppressive effects. It is likely that MDSC activation via TLR play especially important role during pathogenic infections.

Figure 3. Suppressive mechanisms mediated by different subsets of MDSCs

Myeloid-derived suppressor cells (MDSCs) consist of two major subsets: granulocytic MDSCs with a CD11b⁺Ly6G⁺Ly6C^low phenotype and monocytic MDSCs with a CD11b⁺Ly6G^-Ly6C^high phenotype. In most tumour models, it is predominantly (70–80%) the granulocytic subset of MDSCs that expands. We hypothesize that the granulocytic subset of MDSCs has increased activity of STAT3 (signal transducer and activator of transcription 3) and NADPH, which results in high levels of reactive oxygen species (ROS) but little nitric oxide (NO) production. ROS and, in particular, peroxynitrite (the product of a chemical reaction between superoxide and NO) induces post-translational modification of T-cell receptors and may cause antigen-specific T-cell unresponsiveness. The monocytic MDSC subset has upregulated expression of STAT1 and inducible nitric oxide synthase (iNOS) and increased levels NO but little ROS production. NO, which is produced by the metabolism of L-arginine by iNOS, suppresses T-cell function through a variety of different mechanisms that involve the inhibition of Janus kinase 3 (JAK3) and STAT5, the inhibition of MHC class II expression and the induction of T-cell apoptosis. Both subsets have elevated level of arginase 1 (ARG1) activity that causes T-cell suppression through depletion of arginine. Only monocytic MDSCs can differentiate into mature dendritic cells and macrophages in vitro.

Figure 4. The mechanisms of MDSC-mediated immune suppression differ in lymphoid organs and at the site of a tumour

Myeloid-derived suppressor cells (MDSCs) migrate to tumour sites and peripheral lymphoid organs. (a) In peripheral lymphoid organs, MDSCs produce high levels of reactive oxygen species (ROS), including peroxynitrite, and upregulate signal transducer and activator of transcription 3 (STAT3) activity. This is associated with a moderate increase in arginase activity and relatively low level of nitric oxide (NO) production. MDSCs are able to take up, process and present antigens to antigen-specific CD8⁺ T cells. During this close cell–cell contact, peroxynitrite produced by MDSCs causes nitration and nitrosylation of different amino acids in the T-cell receptor (TCR) and CD8 molecules on the surface of T cells, which causes the T cells to become unresponsive to specific antigen stimulation. However, these cells retain the ability to respond to non-specific stimulation with CD3- and CD28-specific antibodies. (b) By contrast, MDSCs that migrate to the tumour site upregulate STAT1 activity, produce high levels of inducible nitric oxide synthase (iNOS), NO and arginase. This is associated with low levels of ROS. High amounts of arginase and NO that are released from MDSCs inhibit T-cell function in a nonspecific manner. MDSCs at the tumour site can also differentiate to tumour-associated macrophages (TAMs). In contrast to MDSCs, TAMs upregulate the expression of either arginase or iNOS, depending on the nature of the tumour microenvironment (see REF 91), but not of both proteins. TAMs acquire ability to produce several suppressive cytokines. Together with MDSCs, TAMs contribute to nonspecific T-cell suppression in the tumour microenvironment.