Myeloid-Derived Suppressor Cells in Colorectal Cancer

Abstract

Colorectal cancer (CRC) remains one of the most common malignancies diagnosed worldwide. The pathogenesis of CRC is complex and involves, among others, accumulation of genetic predispositions and epigenetic factors, dietary habits, alterations in gut microbiota, and lack of physical activity. A growing body of evidence suggests that immune cells play different roles in CRC, comprising both pro- and anti-tumorigenic functions. Immunosuppression observed during cancer development and progression is a result of the orchestration of many cell types, including myeloid-derived suppressor cells (MDSCs). MDSCs, along with other cells, stimulate tumor growth, angiogenesis, and formation of metastases. This article focuses on MDSCs in relation to their role in the initiation and progression of CRC. Possible forms of immunotherapies targeting MDSCs in CRC are also discussed.

Keywords: T regulatory cells (Tregs); arginase-1 (ARG1); colorectal cancer (CRC); inducible NO synthase (iNOS); myeloid-derived suppressor cells (MDSCs).

Figure 1

Crosstalk between MDSCs and other cells in the cancer microenvironment (created with BioRender.com). Factors like PGE2, IL-6, IL-10, and LTB4 are involved in the induction of MDSCs, where IL-10 can also be involved in the generation of Mo-MDSCs from circulating blood monocytes. In addition, NO produced by iNOS is required for the production of N-CCL2 from CCL2, acting as a chemoattractant for monocytes. In a similar manner, CXCL1 and CXCL2 binding to CXCR2 may recruit MDSCs to the tumor bed. Simultaneously, exosomes containing exosomal S100A9 protein are released by PMN-MDSCs, supporting the tumor growth. On the other hand, EVs generated by the tumor transfer biologically active tumor-related factors, e.g., proteins and miRNAs, which may also be involved in the induction of MDSCs from infiltrating monocytes. Moreover, hypoxia per se and hypoxia-related factors, including HIF1a, are also responsible for the induction of the expression of suppressive molecules such as VISTA or PD-L1 on the surface of MDSCs, which act through VISTA receptor and PD-1 on the T cells, respectively. TGFβ produced by MDSCs has a number of suppressive actions, e.g., MDSCs, through TGFβ, can induce the epithelial to mesenchymal cell transition (EMT) process, which is essential for metastasis formation, or inhibit NK cells. Moreover, TGFβ has a great influence, together with IL-10, on the induction of Tregs, while Tregs, producing TGFβ, induce in return MDSCs as a result of a positive feedback loop. In addition, MDSCs may also inhibit the production of antibodies and T cells directed against tumor-associated antigens (TAA), such as MUC1. Additionally, NO, O2-, and a reduced concentration of L-arginine, which are associated with MDSC activity in the tumor microenvironment, inhibit T-cell proliferation. Moreover, NO by itself can modify TCR structure and induce T-cell apoptosis.