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

Abstract

Fibroblasts and macrophages play key roles in the development of hepatocellular carcinoma (HCC). However, crosstalk 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 CAF to mediate M2 polarization of macrophages. The fully human antibody IgG78 bound glycosylated endosialin and induced its internalization in CAF, thus weakening the crosstalk between CAF 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 CAF promote HCC progression and highlight IgG78 as a promising therapeutic candidate for HCC treatment.