Journal Article

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

Lim, Seung-Oe, Khoo, Kay-Hooi, Wu, Yun, Yamaguchi, Hirohito, Yao, Jun, Chang, Shih-Shin, Ding, Qingqing, Hung, Mien-Chie, Allison, James P., Chan, Li-Chuan, Lee, Cheng-Chung, Hortobagyi, Gabriel N., Lee, Heng-Huan, Wu, Hsing-Ju, Wang, Yan, Yu, Dihua, Hsu, Jung-Mao, Sahin, Aysegul A., Hsu, Jennifer L., Li, Chia-Wei, Kuo, Chu-Wei, Kim, Taewan, Xia, Weiya, Cha, Jong-Ho

2016

Overview

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 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. Programmed Death ligand-1 (PD-L1) protein mediates immune suppression in cancer. Here, the authors show that in breast cancer, PD-L1 expression can be up regulated post-translationally by glycosylation, which in turn acts through inhibiting GSK3β-mediated PD-L1 degradation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 14/1 / 38/70 / 631/250/580 / 631/67/1059/2325 / 631/67/1347 / 631/80/458/1524 / 64 / 64/60 / 82/58 / Animal models / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Apoptosis / B7-H1 Antigen - immunology / B7-H1 Antigen - metabolism / beta-Transducin Repeat-Containing Proteins - metabolism / Breast - pathology / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - immunology / Breast Neoplasms - pathology / Cancer / Cell death / Cell Line, Tumor / Deactivation / Epidermal growth factor / Epidermal Growth Factor - metabolism / Female / Gefitinib / Glycogen / Glycogen synthase kinase 3 / Glycogen Synthase Kinase 3 beta - metabolism / Glycosylation / Growth factors / Humanities and Social Sciences / Humans / Immunity / Immunologic Surveillance - immunology / Immunosuppression / Inactivation / Kinases / Ligands / Lymphocyte Activation - immunology / Lymphocytes T / Mice / Mice, Inbred BALB C / Mortality / multidisciplinary / PD-1 protein / PD-L1 protein / Phosphorylation / Programmed Cell Death 1 Receptor - metabolism / Proteasomes / Protein Stability - drug effects / Proteins / Quinazolines - pharmacology / Quinazolines - therapeutic use / Science / Science (multidisciplinary) / Signal transduction / T-Lymphocytes - drug effects / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Tumor Escape - immunology / Tumors / Ubiquitination / Xenograft Model Antitumor Assays