The mononuclear phagocyte system in hepatocellular carcinoma

Figure 1  The interaction of mononuclear phagocyte system and hepatocellular carcinoma in the tumor microenvironment. (1) Activated monocytes secrete TNF-α and IL-10 to increases the expression of PD-L1 on the surface of monocytes, inhibiting the function of Tumor-specific T cell. TNF-α, CXCL2 and CXCL8 produced by monocytes stimulate neutrophils to produce MSO which promote tumor development; (2) Tumor-derived growth factors stimulate myeloid-derived suppressor cell differentiation through STAT3, IRF8, A2B, NLRP3 pathways and PEG2, COX2 produced by tumor stroma stimulate myeloid-derived suppressor cell differentiation through NK-κB, STAT1, STAT6 pathways. Myeloid-derived suppressor cell promotes tumor progression by producing VEGF, BV8 and MMP9. Myeloid-derived suppressor cells inhibits the function of NK cells and CD8+ T cells. Reactive oxygen species induce the expression of CD155 on myeloid-derived suppressor cells inhibiting natural Killer cell function; (3) The exosomes PKM2 produced by hepatocellular carcinoma in tumor microenvironment mediate the production of CXCL2 and CXCL8 through the PFKFB3-NF-κB signaling pathway; (4) Monocytes in peripheral blood mononuclear cells differentiate into macrophages through STAT3 pathway. LPS and IFN-γ stimulated tumor-associated macrophages polarizing into M1 phenotype, but IL-4, IL-8, IL-10, IL-13, CSF-1 and CCL2 stimulated tumor-associated macrophages polarizing into M2 phenotype through c-Mcy, NFκB and MAPK signaling pathway; and (5) Monocytes in peripheral blood mononuclear cells can be differentiated into immature dendritic cell, loaded with antigen to produce mature dendritic cell. Tumor-derived exosomes impair the activation and maturation of dendritic cells through IL-6 STAT3 signaling pathway. HCC: Hepatocellular carcinoma; MDSC: Myeloid-derived suppressor cells; iDC: Immature dendritic cell; mDC: Mature dendritic cell; M1: M1-type macrophages; M2: M2-type macrophages; ROS: Reactive oxygen species.