Cancer therapy research landscape has been changed significantly after the discovery of immune checkpoint inhibitors which are effective in inducing anti-cancer immune response. Among these, anti-PDL-1/PD-1 antibodies provide a robust anti-tumor response in patients with metastatic solid tumors. PD-1 (programmed cell death-1) expressed on T cells binds programmed cell death ligand (PDL-1) in cancer cells to prevent anti-tumor functions of T cells. PDL-1 is a transmembrane protein highly expressed in cancer cells to evade the host immune. system. In addition to its effects on the cell membrane to inhibit anti-tumor functions of T cells, PDL-1 was shown to exert pro-survival and pro-metastatic effects by inducing intracellular inflammasome signaling. The mechanisms that regulate the intracellular signaling activity of PDL-1, however, are understudied in cancer models. Here, we report a novel mechanism whereby internalization of PDL-1 in response to alterations of lipid/ceramide metabolism induces sonic-hedgehog (Shh) signaling to enhance tumor metastasis, which are highly resistant to immunotherapy.
Hollings Cancer Center
Besim Ogretmen is director at the “Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina.” Also he is a leader in the Developmental Cancer Therapeutics Program, Hollings Cancer Center, Medical University of South Carolina.”
Dr. Ogretmen’s research is focused on deciphering the regulation and function of bioactive sphingolipids, specifically ceramide and sphingosine-1-phosphate, in cancer development/progression and therapy. Specifically, he investigates the roles and mechanisms of action of ceramide, an emerging tumor suppressor lipid which induces antiproliferative and apoptotic responses. The long-term goal of these studies is to develop mechanism-based therapeutic strategies against human cancers.