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

Nat Commun. 2016 Aug 30;7:12632. doi: 10.1038/ncomms12632.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism*
  • Breast / pathology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Epidermal Growth Factor / metabolism
  • Female
  • Gefitinib
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Glycosylation
  • Humans
  • Immunologic Surveillance / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Phosphorylation
  • Programmed Cell Death 1 Receptor / metabolism
  • Protein Stability / drug effects
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tumor Escape / immunology*
  • Ubiquitination
  • Xenograft Model Antitumor Assays
  • beta-Transducin Repeat-Containing Proteins / metabolism

Substances

  • Antineoplastic Agents
  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Quinazolines
  • beta-Transducin Repeat-Containing Proteins
  • Epidermal Growth Factor
  • Glycogen Synthase Kinase 3 beta
  • Gefitinib