Skip to main content
. 2023 Jul 31;15(15):3898. doi: 10.3390/cancers15153898

Figure 2.

Figure 2

Cancer cells shape the tumor microenvironment through secretion of soluble factors and recruitment of immunosuppressive cells. Neutrophils and monocytes migrate to TME attracted by chemokines such as CXCL12 and CXCL1, released by cancer cells, and differentiate into polymorphonuclear (PMN−) and mononuclear (M−) MDSCs. PMN-MDSCs suppress immune cells by producing ROS, peroxinitrite and prostaglandins and depleting TME of arginine by upregulating arginase I expression. M-MDSCs inhibit T cells, B cells and natural killer (NK) cells by producing nitric oxide (NO), immunosuppressive IL-10 and TGFβ and immune checkpoint molecules such as PDL1. Chemokine and growth factors (VEGF, CCL2, CCL5, CSF-1, EMAP-II, endothelin-2, SEMA3A, oncostatin M, and eotaxin), secreted by cancer cells, promote the migration of monocytes into the TME and their differentiation into tumor-associated macrophages (TAMs). TAMs differentiate into anti-tumor M1 macrophages upon stimulation with IFN-γ, lipopolysaccharide, IL-1β, TNF and/or GM-CSF, and into pro-tumor M2 macrophages upon stimulation with IL-4, IL-10, IL-13 and/or M-CSF. Tumor antigens, cytokines (such as TGF-B) promote CD4 differentiation in immunosuppressive Treg and T helper type 2 cells (Th2). Th2 cells secrete protumor cytokines IL-4, IL-5, IL-10, IL-13, and IL-17, recruits M2 macrophages by releasing IL-5 and IL-13 and promotes MDSCs infiltration by increasing vascular leakage through IL17 secretion. Tregs impair CTL, NK and dendritic cell function by secreting immunosuppressive cytokines such as IL-10, TGF-β and IL-35, expressing the immune checkpoint receptor (LAG3, CTLA4) the enzyme IDO, which converts tryptophan to kynurenine and CD39 and CD73 nucleases that convert ATP to adenosine.