CD146 contributes the metastatic properties and antitumor immunity of human colon adenocarcinoma cells

Abstract

CD146 (MCAM) expressed on not only vascular endothelial and smooth muscle cells but also various malignant tumor cells. It has been shown that overexpression of CD146 predicts poor prognosis of solid tumor. Several reports by using transfectants or gene silencing technique have shown that CD146 is involved in cell adhesion and inflammatory cell migration. However, contribution of CD146 in tumor metastasis and antitumor immunity are still unknown. To investigate the effect of CD146 on tumor metastatic properties, we establish two subclones from DLD-1 (human colon adenocarcinoma cells) expressing CD146 or not. Both cell lines express epithelial tumor marker EpCAM and TROP2 equally, while CD146 (+) DLD-1 could only express CD44 variant v8–v10 and EphA2. Using metabolic assay, we found enhanced metabolism and decreased lactate production in CD146 (+) DLD-1. Consist with the morphological changes to mesenchymal features CD146 (+) DLD-1, the expression of E-cadherin and claudin-3 in tight junction were decreased in CD146 (+) DLD-1. In addition, CD146 (+) DLD-1 significantly increased the production of VEGF and the induction of various genes (slug, twist and zeb1) which are involved in epithelial to mesenchymal transition (EMT). Interestingly, the expression of immune checkpoint molecules including B7-H1, B7-DC (both PD-1 ligands), CD155 and IDO were up-regulated in CD146 (+) DLD-1 inducing the resistance of cytotoxic effect of activated lymphocytes. These results indicate that CD146 (+) DLD-1 strongly induces immune escape mechanism, thus demonstrating a new relationship between CD146 and EMT and anti-tumor immunity, which would be a new treatment and diagnostic target for immunotherapy.