Targeting Myeloid-Derived Suppressor Cells to Enhance the Antitumor Efficacy of Immune Checkpoint Blockade Therapy

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are activated under pathological conditions, such as cancer, or mature myeloid cells that are converted immune-suppressive cells via tumor-derived exosomes, and potently support the tumor processes at different levels. Currently, multiple studies have demonstrated that MDSCs induce immune checkpoint blockade (ICB) therapy resistance through their contribution to the immunosuppressive network in the tumor microenvironment. In addition, non-immunosuppressive mechanisms of MDSCs such as promotion of angiogenesis and induction of cancer stem cells also exert a powerful role in tumor progression. Thus, MDSCs are potential therapeutic targets to enhance the antitumor efficacy of ICB therapy in cases of multiple cancers. This review focuses on the tumor-promoting mechanism of MDSCs and provides an overview of current strategies that target MDSCs with the objective of enhancing the antitumor efficacy of ICB therapy.

Keywords: immune checkpoint blockade (ICB) therapy; immunosuppression; myeloid-derived suppressor cells (MDSCs); programmed cell death protein 1 (PD-1); the tumor microenvironment (TME).

Figure 1

MDSCs-mediated inhibition of T cell. MDSCs induce nitration of TCR-CD8 complex through hyperproduction of reactive oxygen species (ROS) and peroxynitrite (PNT) and nitrate lymphocyte-specific protein tyrosine kinase (LCK) at Tyr394 and CCL2 chemokine through reactive nitrogen species (RNS), which inhibit T cell recognition of tumor antigen, and lead to reduced interleukin 2 (IL2) production and T-cell infiltration. MDSCs deplete extracellular L-arginine (L-Arg) by expressing arginase-1(Arg-1) and cationic amino acid transporter 2 (Cat2), which block the re-expression of CD3zeta, inhibit antigen-specific T-cell proliferation, and result in cell cycle arrest through upregulation of cyclin D3 and cyclin-dependent kinase 4 (cdk4). MDSCs also limit the availability of cysteine and tryptophan by expressing the xc-transporter and IDO, respectively, which block T-cell activation. On the one hand, MDSCs trigger apoptosis of tumor-infiltrating CTLs through the Fas/Fas-ligand axis. On the other hand, MDSCs express the death receptor Fas and apoptose in response to T-cell-expressed FasL. MDSCs induce DNA damage and subsequent p53 pathway activation through an iNOS-dependent pathway, thus inducing apoptosis of CD8+ T cells.

Figure 2

Multiple immunosuppressive mechanisms of MDSCs on NK, DCs, Th17, Tregs. MDSCs directly inhibit autologous natural killer (NK) cell cytotoxicity and cytokine secretion by interaction with the NKp30 on NK cells. Also, MDSCs indirectly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity (ADCC), cytokine production, and signal transduction through the production of NO, TGFβ, and H2O2. Immature NK cells can be converted into MDSCs by tumor-derived GM-CSF. MDSCs activate NK cells to produce high amounts of IFN‐γ, which depends partially on the interaction of NKG2D on NK cells with NKG2D ligand RAE-1 on MDSCs and the IFNAR pathway. MDSCs inhibited IL-12 production of DCs by IL-10 and suppressed T-cell stimulatory activity of DCs. Myeloperoxidase (MPO)-driven lipid peroxidation in PMN-MDSCs blocked cross-presentation by DCs. Arg1-dependent production of polyamines by MDSCs conditioned DCs toward an immunosuppressive phenotype via activation of the Src kinase. S100A8 and S100A9 produced by MDSCs inhibited DCs differentiation from hematopoietic progenitor cells (HPCs) via persistent upregulation of ROS. MDSCs secrete Th17-driving cytokines (IL-1β, IL-6, and IL-23) and produce NO and Prostaglandin-E2 (PGE2) to facilitate Th17 cells differentiation; the latter required nitric oxide synthase (NOS) and cyclooxygenase 2 (COX-2) activity. Additionally, MDSCs promote the recruitment of Th17 cells through CCL4 and induce secretion of IL-17 by CD4(+) T cells through secretion of IL-1β. MDSCs induce Foxp3+ Tregs from naive CD4+ T cells and monocyte-induced Th17 cells via MDSCs-derived TGF-β and retinoic acid. PGE2 produced by MDSCs expand IL-10-producing Treg subsets.

Figure 3

MDSCs promote angiogenesis and induce cancer stem cells (CSCs) in the TME. MDSCs contribute to tumor vascularization by producing high levels of matrix metalloproteinase 9 (MMP9). MDSCs directly produce angiogenic factors, including VEGF and bFGF through Stat3 activation to induce angiogenesis. MDSCs control the expression of CD31 and CD117 through the expression of the Wilms’ tumor suppressor Wt1, causing tumor vascularization. MDSCs shift the IFNγ/IL6 balance to promote neovascularization through IDO1 signaling. MDSCs-secreted S100A8 and S100A9 stimulate angiogenesis. Exosomes miR-126a released from MDSCs promote tumor angiogenesis. MDSCs differentiate into endothelial cells (ECs). MDSCs endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/Notch cross-talk signaling and to epithelial ovarian cancer (EOC) cells by the colony-stimulating factor 2 (CSF2)/p-STAT3 signaling pathway. MDSCs also trigger the expression of miRNA101 and piRNA-823 to promote the stemness of ovarian carcinoma cells and myeloma (MM) cells, respectively. MDSCs can indirectly modulate the stemness of tumor cells through the secretion of various factors such as exosomal S100A9, TGF-β1, PGE2, MMP9, and chitinase 3-like 1 (CHI3L1).