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

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

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
2
Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
3
Core Facilities for Protein Structural Analysis, Academia Sinica, Taipei 115, Taiwan.
4
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
5
Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
6
Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
7
Department of Biotechnology, Asia University, Taichung 413, Taiwan.
8
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
9
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
10
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

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.

PMID:
27572267
PMCID:
PMC5013604
DOI:
10.1038/ncomms12632
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

M.-C.H. received sponsored research agreement from STCube Pharmaceuticals Inc. through MD Anderson Cancer Center. C.-W.L., S.-O.L. and M.-C.H. are inventors on patent applications under review: Dual function antibodies specific to glycosylated PD-L1 and methods of use thereof, 2016, No. 62/314,652. Combination treatments directed toward programmed death ligand-1 (PD-LI) positive cancers, 2016, No. 62/316,178. Antibodies specific to glycosylated PD-L1 and methods of use thereof, 2016, No. PCT/US16/24691. The remaining authors declare no competing financial interests.

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