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

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. Hortobagyi and Mien-Chie Hung ()
Additional contact information
Chia-Wei Li: The University of Texas MD Anderson Cancer Center
Seung-Oe Lim: The University of Texas MD Anderson Cancer Center
Weiya Xia: The University of Texas MD Anderson Cancer Center
Heng-Huan Lee: The University of Texas MD Anderson Cancer Center
Li-Chuan Chan: The University of Texas MD Anderson Cancer Center
Chu-Wei Kuo: Core Facilities for Protein Structural Analysis, Academia Sinica
Kay-Hooi Khoo: Institute of Biological Chemistry, Academia Sinica
Shih-Shin Chang: The University of Texas MD Anderson Cancer Center
Jong-Ho Cha: The University of Texas MD Anderson Cancer Center
Taewan Kim: The University of Texas MD Anderson Cancer Center
Jennifer L. Hsu: The University of Texas MD Anderson Cancer Center
Yun Wu: The University of Texas MD Anderson Cancer Center
Jung-Mao Hsu: The University of Texas MD Anderson Cancer Center
Hirohito Yamaguchi: The University of Texas MD Anderson Cancer Center
Qingqing Ding: The University of Texas MD Anderson Cancer Center
Yan Wang: The University of Texas MD Anderson Cancer Center
Jun Yao: The University of Texas MD Anderson Cancer Center
Cheng-Chung Lee: Core Facilities for Protein Structural Analysis, Academia Sinica
Hsing-Ju Wu: Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University
Aysegul A. Sahin: The University of Texas MD Anderson Cancer Center
James P. Allison: The University of Texas MD Anderson Cancer Center
Dihua Yu: The University of Texas MD Anderson Cancer Center
Gabriel N. Hortobagyi: The University of Texas MD Anderson Cancer Center
Mien-Chie Hung: The University of Texas MD Anderson Cancer Center

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12632

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