Impacts of Globo H Ceramide on Tumor Microenvironment

Although cancer immunotherapy has been flourishing, the number of targets for Food and Drug Administration (FDA)-approved cancer immunotherapeutics has remained small and mostly limited to proteins. The approval of dinutuximab, an anti-GD2 for treating high-risk neuroblastoma in 2015, marks the first new agent targeting glycosphingolipids (GSLs). Recently, our research group demonstrated that another GSL, Globo H ceramide (GHCer), which was previously reported to be the most prevalent cancer-associated antigen in many epithelial cancers, is an independent poor prognostic factor for breast cancer, hepatoma, cholangiocarcinoma, and gallbladder cancer. We had further shown that GHCer is shed from tumor cells to extracellular vesicles (EVs), which are then incorporated into endothelial cells in the tumor microenvironment to promote angiogenesis. Molecular dynamics simulation and other studies also revealed fucose-dependent changes in the glycan conformation of GHCer conducive for a complex formation between translin-associated factor X (TRAX) protein and GHCer, thus highlighting the molecular mechanism of how GHCer facilitated dissociation of phospholipase C beta 1 (PLCβ1) from TRAX, thereby enhancing angiogenesis. Thus, GHCer is not only a tumor antigen associated with adverse prognostic impact but also acts as an immune checkpoint and an angiogenic factor to shape the tumor microenvironment. These findings provide strong rationales for developing Globo H-targeted immunotherapy.