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.