Abstract
Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumor-associated immune escape. Despite efforts to limit the interaction between cancer cells and immune cells, the molecular mechanism by which cancer cells initiate immune escape is less understood. Here, we show that the immunosuppression activity of PD-L1 is stringently modulated by the spatial competition between ubiquitination and N-glycosylation. We identified glycogen synthase kinase 3β (GSK3β) as a novel protein that interacts with PD-L1 and can induce phosphorylation-dependent proteasome degradation by β-TrCP. In depth analysis of PD-L1 N192, N200, and N219 glycosylation suggests glycosylation antagonizes GSK3β binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3β and β-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3β inactivation in basal-like breast cancer (BLBC). Inhibition of EGF signaling by gefitinib destabilizes PD-L1, enhances antitumor T cell immunity, and sensitizes BLBC cells to PD-1 blockade. Together, our results link ubiquitination and glycosylation pathways with stringent regulation of PD-L1, which could open new therapeutic strategies to enhance cancer immune therapy efficacy.
Citation Format: Seung-Oe Lim, Chia-Wei Li, Mien-Chie Hung. Stabilization of programmed death ligand-1 by epidermal growth factor enhances cancer cell immune escape. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B47.
