Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity

• DOI: 10.1038/ncomms12632
• Publication Date: 2016-08-30T10:26:05Z
• Authors: Chia-Wei Li; Seung-Oe Lim; Weiya Xia; Heng-Huan Lee; Li-Chuan Chan; Chu-Wei Kuo; Kay-Hooi Khoo; Shih-Shin Chang; Jong-Ho Cha; Taewan Kim; Jennifer L. Hsu; Yun Wu; Jung-Mao Hsu; Hirohito Yamaguchi; Qingqing Ding; Yan Wang; Jun Yao; Cheng-Chung Lee; Hsing-Ju Wu; Aysegul A. Sahin; James P. Allison; Dihua Yu; Gabriel N. Hortob...; Mien-Chie Hung
• Keywords: 0301 basic medicine; Glycosylation; Science; Programmed Cell Death 1 Receptor; Antineoplastic Agents; Breast Neoplasms; Lymphocyte Activation; Article; B7-H1 Antigen; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Breast; Phosphorylation; Immunologic Surveillance; Mice, Inbred BALB C; Glycogen Synthase Kinase 3 beta; Epidermal Growth Factor; Protein Stability; Q; Gefitinib; 3. Good health; Quinazolines; Female

AbstractExtracellular 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 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. In-depth analysis of PD-L1 N192, N200 and N219 glycosylation suggests that 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. 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.