Immunotherapy Targeting Myeloid-Derived Suppressor Cells (MDSCs) in Tumor Microenvironment

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate in tumor-bearing hosts to reduce T cells activity and promote tumor immune escape in the tumor microenvironment (TME). The immune system in the TME can be stimulated to elicit an anti-tumor immune response through immunotherapy. The main theory of immunotherapy resides on the plasticity of the immune system and its capacity to be re-educated into a potent anti-tumor response. Thus, MDSCs within the TME became one of the major targets to improve the efficacy of tumor immunotherapy, and therapeutic strategies for tumor MDSCs were developed in the last few years. In the article, we analyzed the function of tumor MDSCs and the regulatory mechanisms of agents targeting MDSCs in tumor immunotherapy, and reviewed their therapeutic effects in MDSCs within the TME. Those data focused on discussing how to promote the differentiation and maturation of MDSCs, reduce the accumulation and expansion of MDSCs, and inhibit the function, migration and recruitment of MDSCs, further preventing the growth, invasion and metastasis of tumor. Those investigations may provide new directions for cancer therapy.

Keywords: cancer; inhibitory factors; myeloid-derived suppressor cells; tumor immunotherapy; tumor microenvironment.

Figure 1

Multiple MDSC-mediated immunosuppressive mechanisms. MDSCs suppressed T cell function through multiple mechanisms. Several factors were involved in triggering signaling pathway, such as STAT1, STAT3, STAT6 and MyD88, which led to high expression level of immunosuppressive factors, such as Arg-1, iNOS, ROS, NO, which suppress T cells response. C/EBPβ was one of the family of CCAAT/enhancer-binding proteins (C/EBPs) which belonged to transcription factors (TFs), which had three isoforms, LAP*, LAP and LIP. S100A8 and S100A9 along with gp91phox (also known as CYBB) were part of the NADPH oxidase (NOX) complex that was responsible for the increased production of reactive oxygen species (ROS) in MDSCs. ADAM17, disintegrin and metalloproteinase domain 17; JAK, Janus kinase; STAT, signal transducer and activator of transcription; PNT, peroxynitrate; COX2, cyclooxygenase-2; APC, antigen-presenting cell; MMP9, matrix metalloproteinase 9; MyD88, myeloid differential protein-88; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating; BCL-XL, B-cell lymphoma XL; GAL9, galectin 9; TIM3, T cell immunoglobulin and mucin domain-containing protein 3.

Figure 2

Multiple agents regulated the maturation and differentiation of MDSCs. The differentiation and maturation of MDSCs were regulated by multiple agents, such as RUNX1, ATRA, IL-12, CCL5, and CpG oligonucleotides as well as miRNA, lncRNA. ATRA, all-trans retinoic acid (ATRA).

Figure 3

Resistance mechanisms to MDSC immunosuppression. AMPK activation inhibited the TLR4/Myd88 pathway as well as STATs and NF-κB pathways to attenuate the immunosuppressive function of tumor MDSCs; miR-15 family including miR-15a, miR-15b, miR-16, miR-195, and miR-503, down-regulated the suppressive function of MDSCs and/or Tregs within the TME through blocking PD-L1/PD-1 signaling pathway; miR-155 regulated tumor MDSC via the repression of SOCS-1 in MDSCs; Nrf2 activation reduced intracellular ROS production to abrogate MDSC immunosuppression; DATS, as H2S donors and an activator of CSE reduced the number of MDSCs in spleen and blood through the inhibition of iNOS expression and NO production; Lnc-C/EBPβ mastered suppressive functions and differentiation of MDSCs by binding to C/EBPβ (specifically to the LIP isoform). AMPK, AMP-activated protein kinase; C/EBPs, CCAAT/enhancer-binding proteins; miRNA, MicroRNA; LncRNAs, long non-coding RNAs; MALAT1, metastasis associated lung adenocarcinoma transcript 1; DATS, diallyl trisulfide.