Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms12632
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Funding
- National Institutes of Health [R01 CA109311, PO1 CA099031, CCSG CA016672]
- National Breast Cancer Foundation Inc.
- Breast Cancer Research Foundation
- Patel Memorial Breast Cancer Endowment Fund
- University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund
- Ministry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE) [MOST105-2911-I-002-302]
- Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence [MOHW105-TDU-B-212-134003]
- Center for Biological Pathways
- Susan G. Komen for the Cure Postdoctoral Fellowship [PDF12231298]
- Basic Science Research Program through the National Research Foundation of Korea - Korea government (MSIP) [NRF-2011-357-C00140]
- National Research Foundation of Korea (NRF) grant for the Global Core Research Center (GCRC) - Korea government (MSIP) [2011-0030001]
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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 3 beta (GSK3 beta) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by beta-TrCP. In-depth analysis of PD-L1 N192, N200 and N219 glycosylation suggests that glycosylation antagonizes GSK3 beta binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3 beta and beta-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3 beta 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.
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