MDSC-Mediated Mechanisms of Immunosuppression

Myeloid-derived Suppressor Cell (MDSC)-Mediated Mechanisms of Immunosuppression

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of early myeloid cells that accumulate during chronic inflammation, autoimmunity, infection, and cancer. Under healthy conditions, these precursor cells terminally differentiate into mature dendritic cells, granulocytes, and macrophages, but under pathological conditions, their differentiation is partially blocked, leading to an accumulation of the immature cells. Immature myeloid cell accumulation is of significant interest as these cells (now known as MDSCs) have immunosuppressive properties and are thought to play a key role in inhibition of the anti-tumor immune response. As a result, they are considered to be a major obstacle for cancer immunotherapy.

Amino Acid Depletion and Production of Immunosuppressive Metabolites by MDSCs

MDSCs inhibit the anti-tumor immune response through multiple mechanisms. One mechanism is through the depletion of amino acids and the production of immunosuppressive metabolites. MDSCs produce high levels of intracellular arginase 1 (ARG1), which leads to increased uptake of L-arginine and depletion of this amino acid from the environment. In the presence of low levels of L-arginine, T cells display reduced expression of TCR-CD3 zeta chain and undergo proliferative arrest. Additionally, MDSCs sequester cystine, which limits its availability to be taken up by antigen-presenting cells (APCs) and subsequently reduced and exported as cysteine. Unlike APCs, MDSCs are capable of importing cystine but they fail to export cysteine due to a lack of the ASC transporter. A reduction in cysteine levels is problematic for T cells, which are unable to generate their own cysteine due to the absence of cystathionine gamma-lyase, an enzyme required for the breakdown of cystathionine into cysteine, and the lack of a functional xc- cystine transporter. As a result, T cells rely on other cells to provide cysteine for their survival. Since cysteine is most highly required during T cell activation and subsequent proliferation and differentiation, it is typically provided to T cells by APCs during antigen presentation. In the presence of MDSCs, however, the levels of cystine imported and cysteine produced by APCs is reduced, thereby compromising T cell activation. MDSCs can also inhibit immune cell functions through the degradation of L-tryptophan. MDSCs express indolamine-2,3-dioxygenase (IDO), which catalyzes the initial, rate-limiting step in L-tryptophan degradation by the kynurenine pathway. The degradation of L-tryptophan and the presence of kynurenine and its derivatives inhibit the proliferation and activity of CD4⁺ and CD8⁺ T cells and natural killer cells and promote the differentiation of regulatory T cells (Tregs).

Generation of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) by MDSCs

A second mechanism by which MDSCs inhibit the anti-tumor immune response is by the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Hydrogen peroxide, peryoxynitrite, and nitric oxide (NO) are produced by MDSCs through the activities of NADPH oxidase, arginase-1, and iNOS. These molecules have a variety of immunosuppressive effects on T cells. Hydrogen peroxide promotes loss of TCR-CD3 zeta chain expression and promotes T cell proliferative arrest and apoptosis. Nitric oxide inhibits IL-2 signaling and T cell proliferation and migration, and peryoxynitrite promotes T cell apoptosis, along with nitration or nitrosylation of multiple target molecules including TCR, CD3, CD8, and CCL2, which inhibits T cell activation and intra-tumoral migration.

Direct Engagement of T cell Inhibitory and Apoptotic Receptors by MDSCs

MDSCs may also suppress T cell functions through the direct engagement of T cell inhibitory and apoptotic receptors. In some tumors, activated MDSCs express high levels of PD-L1, Fas Ligand (Fas L), and Galectin-9. Interactions of these ligands with their respective T cell expressed receptors, PD-1, Fas/CD95, or Tim-3 has been shown to lead to either T cell exhaustion in the case of PD-L1/PD-1 or T cell apoptosis in the case of Fas L/Fas and Galectin-9/Tim-3.

Production of Inhibitory Cytokines by MDSCs

MDSCs also mediate immunosuppression through the production of IL-10 and TGF-beta 1. Together these cytokines inhibit the activation, differentiation, and proliferation of effector T cells, as well as inhibit cytokine production by these cells. Additionally, IL-10 and TGF-beta 1 promote the expansion of suppressive T cells. TGF-beta 1 induces the expression of FoxP3 in CD4⁺CD25^- conventional T cells to promote a suppressor cell phenotype in these cells, while IL-10 promotes the conversion of activated conventional T cells to IL-10-, TGF-beta 1-secreting Tr1 cells. In addition to its effects on T cells, TGF-beta 1 also down-regulates the expression of NKG2D and NKp30 on natural killer (NK) cells and CD8⁺ T cells, reduces NK cell proliferation and cytotoxicity, promotes the polarization of macrophages toward a M2 phenotype, and inhibits dendritic cell (DC) maturation and migration, co-stimulatory molecule expression and IL-12 production.

MDSC-Mediated Inhibition of T Cell Homing to the Lymph Nodes

MDSCs can also inhibit T cell activation by preventing the homing of naïve T cells to the lymph nodes. MDSCs were found to constitutively express Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), also known as TACE, which is a protease that has been shown to cleave L-Selectin/CD62L, among other targets. L-Selectin/CD62L plays a key role in directing antigen-naïve CD4⁺ and CD8⁺ T cells from the blood and lymphatics to the lymph nodes, where they can then become activated. In the presence of MDSCs, L-Selectin/CD62L on naïve T cells is cleaved by ADAM17, thereby preventing their homing and activation.

Production of Extracellular Adenosine by MDSCs

Similar to regulatory T cells (Tregs) and tumor cells themselves, MDSCs have also been shown to express the surface ectonucleotidases, CD39 and CD73, which work in concert to generate extracellular adenosine from ATP. Extracellular adenosine is an immunosuppressive metabolite that signals through the A2a and A2b receptors expressed on different immune cell types to regulate the activities of these cells and drive tumor escape. Adenosine has been shown to inhibit the proliferation and functions of effector T cells, natural killer (NK) cells, and natural killer T (NKT) cells, as well as indirectly affecting T cell functions by acting on antigen-presenting cells. Activation of A2a/A2b receptors on dendritic cells (DCs) promotes their production of immunosuppressive molecules and inhibits their production of IL-12 and TNF-alpha, as well as DC maturation. In addition, adenosine stimulates regulatory T cell (Treg) expansion and increases the suppressive activity of these cells.

Production of PGE₂ by MDSCs

MDSCs also produce prostaglandin E2 (PGE₂) through the up-regulated expression of the PGE₂-producing enzymes, COX2 and PGES1. In an autocrine feedback loop, MDSC-produced PGE₂ signals through its receptors expressed on the surface of MDSCs, to up-regulate their expression of arginase 1 (ARG1) and increase their suppressive activity. Additionally, PGE₂ has been shown to induce MDSC differentiation of bone marrow stem cells, thereby promoting MDSC expansion. Besides its effects on MDSCs themselves, PGE₂ has also been shown to inhibit the cytolytic activity of natural killer (NK) cells and the ability of these cells to produce IFN-gamma. It also inhibits the early stages of dendritic cell differentiation, suppresses IL-2 production and responsiveness in T cells, and inhibits NK/Th1/CD8⁺ T cell-mediated immune responses while promoting Th2/Th17/Treg responses.

S100A8/A9-Mediated Accumulation of MDSCs

MDSCs promote their own accumulation through an S100A8/A9 autocrine feedback loop. MDSCs synthesize and secrete the calcium-binding proteins, S100A8 and S100A9 that bind to carboxylated N-glycans on the receptor for advanced glycation end-products (RAGE) and other glycoproteins receptors expressed on MDSCs. Interactions of S100A8/A9 with these receptors promotes MDSC accumulation and migration. As a result, S100A8/A9 plays a key role in both the generation and recruitment of MDSCs to the tumor microenvironment.

To learn more, explore the following MDSC-related resources:

Current and Emerging Immune Checkpoint Targets for Immuno-Oncology Research eBook
Myeloid-Derived Suppressor Cells (MDSC) research area page
Cell Markers for Myeloid-Derived Suppressor Cell Subsets
Blog Post – Immunology News: Targeting Myeloid-Derived Suppressor Cells (MDSCs) for Cancer Immunotherapy
Myeloid-Derived Suppressor Cells Brochure

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