α1-acid glycoprotein enhances the immunosuppressive and protumor functions of tumor-associated macrophages

Blood levels of acute-phase protein α1-acid glycoprotein (AGP, orosmucoid) increase in patients with cancer. Although AGP is produced from hepatocytes following stimulation by immune cell-derived cytokines under conditions of inflammation and tumorigenesis, the functions of AGP in tumorigenesis and tumor progression remain unknown. In the present study, we revealed that AGP contributes directly to tumor development by induction of programmed death ligand 1 (PD-L1) expression and IL-6 production in macrophages. Stimulation of AGP induced PD-L1 expression in both human monocyte-derived macrophages through STAT1 activation, whereas AGP had no direct effect on PD-L1 expression in tumor cells. AGP also induced IL-6 production from macrophages, which stimulated proliferation in tumor cells by IL-6R-mediated activation of STAT3. Furthermore, administration of AGP to AGP KO mice phenocopied effects of tumor-associated macrophages on tumor progression. AGP decreased IFN-γ secretion from T-cells and enhanced STAT3 activation in subcutaneous tumor tissues. In addition, AGP regulated PD-L1 expression and IL-6 production in macrophages by binding with CD14, a co-receptor for TLR4, and inducing TLR4 signaling. These results provide the first evidence that AGP is directly involved in tumorigenesis by interacting with tumor-associated macrophages and that AGP might be a target molecule for anti-cancer therapy.