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. SahinJames P. Allison, Dihua Yu, Gabriel N. Hortobagyi, Mien Chie Hung

Research output: Contribution to journalArticlepeer-review

404 Citations (Scopus)

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.

Original languageEnglish
Article number12632
JournalNature Communications
Volume7
DOIs
Publication statusPublished - Aug 30 2016
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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