FCGR2A contributes to M2 macrophages polarization in HCC through IL-4/JAK/STAT6 axis

The most common subtype of primary liver cancer is hepatocellular carcinoma (HCC), which accounts for about 90 % of primary liver cancers. Tumor microenvironment (TME) plays important roles in HCC development. TME coexists and interacts with various immune cells. Macrophages are the main components of immune cells in TME. However, the specific mechanism of macrophages in HCC development is not fully understood. We conducted a preliminary study on the gene expression differences between HCC macrophages and paracancer macrophages by single-cell sequencing. Results demonstrated that FCGR2A was highly expressed in liver cancer tissues, and FCGR2A was mainly expressed in M2 macrophages in cancer tissues. The expression level of FCGR2A was correlated with extrahepatic metastasis, maximum tumor diameter, CNLC stage, satellite nodule, and differentiation degree. High FCGR2A expression predicts worse overall survival (OS) and progression-free survival (PFS) in HCC patients. In vivo experiments have verified that both FCGR2A mRNA and protein levels are markedly upregulated in M2 macrophages. Transfection of FCGR2A has been demonstrated to drive the polarization of M2 macrophages through augmenting IL-4 secretion. Further experiments showed that FCGR2A regulated and activated the IL-4/JAK/STAT6 pathway. Inhibition of JAK/STAT6 signaling pathway is capable of counteracting the promoting influence of FCGR2A-induced M2 macrophages on HCC cell proliferation. What's more,macrophages with high FCGR2A expression showed immunosuppressive influence on NK and T cells viabilities and killing activities on HCC tumor cells. Our findings reveal a crucial FCGR2A /IL-4/JAK/STAT6 axis for M2 polarization and provide a rationale for therapeutics of macrophages targeting HCC.