Interaction with CD68 and Regulation of GAS6 Expression by Endosialin in Fibroblasts Drives Recruitment and Polarization of Macrophages in Hepatocellular Carcinoma

Fibroblasts and macrophages play key roles in the development of hepatocellular carcinoma (HCC). However, cross-talk between these two kinds of cells has not been well studied. Endosialin (CD248/TEM1) is a transmembrane glycoprotein that is expressed in certain cancer cells, tumor stromal cells, and pericytes. In this study, we found that endosialin is mainly expressed in cancer-associated fibroblasts (CAF) in HCC and its expression inversely correlates with patient prognosis. Endosialin interacted with CD68 to recruit macrophages and regulated expression of GAS6 in CAFs to mediate M2 polarization of macrophages. The fully human antibody IgG78 bound glycosylated endosialin and induced its internalization in CAFs, thus weakening the cross-talk between CAFs and macrophages. In subcutaneous and orthotopic xenograft models of HCC in nude mice, treatment with IgG78 significantly inhibited tumor growth. These results indicate that endosialin-positive CAFs promote HCC progression and highlight IgG78 as a promising therapeutic candidate for HCC treatment. SIGNIFICANCE: These findings highlight CAF-expressed endosialin as a primary regulator of macrophage recruitment and polarization and demonstrate endosialin inhibition as a potential treatment strategy for HCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3892/F1.large.jpg.