| First Author | Li CW | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 12632 | PubMed ID | 27572267 |
| Mgi Jnum | J:241610 | Mgi Id | MGI:5903179 |
| Doi | 10.1038/ncomms12632 | Citation | Li CW, et al. (2016) Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun 7:12632 |
| abstractText | Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumour-associated immune escape. Here we show that the immunosuppression activity of PD-L1 is stringently modulated by ubiquitination and N-glycosylation. We show that glycogen synthase kinase 3beta (GSK3beta) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by beta-TrCP. In-depth analysis of PD-L1 N192, N200 and N219 glycosylation suggests that glycosylation antagonizes GSK3beta binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3beta and beta-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3beta inactivation in basal-like breast cancer. Inhibition of EGF signalling by gefitinib destabilizes PD-L1, enhances antitumour T-cell immunity and therapeutic efficacy of PD-1 blockade in syngeneic mouse models. Together, our results link ubiquitination and glycosylation pathways to the stringent regulation of PD-L1, which could lead to potential therapeutic strategies to enhance cancer immune therapy efficacy. |
