title: Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity.
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.
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Chia-Wei
authors: CW
authors: Li
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Seung-Oe
authors: SO
authors: Lim
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Weiya
authors: W
authors: Xia
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Heng-Huan
authors: HH
authors: Lee
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors: Li-Chuan
authors: LC
authors: Chan
authors: Core Facilities for Protein Structural Analysis, Academia Sinica, Taipei 115, Taiwan.|Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors: Chu-Wei
authors: CW
authors: Kuo
authors: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors: Kay-Hooi
authors: KH
authors: Khoo
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors: Shih-Shin
authors: SS
authors: Chang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors: Jong-Ho
authors: JH
authors: Cha
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Taewan
authors: T
authors: Kim
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.|Department of Biotechnology, Asia University, Taichung 413, Taiwan.
authors: Jennifer L
authors: JL
authors: Hsu
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Yun
authors: Y
authors: Wu
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Jung-Mao
authors: JM
authors: Hsu
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Hirohito
authors: H
authors: Yamaguchi
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Qingqing
authors: Q
authors: Ding
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Yan
authors: Y
authors: Wang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Jun
authors: J
authors: Yao
authors: Core Facilities for Protein Structural Analysis, Academia Sinica, Taipei 115, Taiwan.
authors: Cheng-Chung
authors: CC
authors: Lee
authors: Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
authors: Hsing-Ju
authors: HJ
authors: Wu
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Aysegul A
authors: AA
authors: Sahin
authors: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: James P
authors: JP
authors: Allison
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors: Dihua
authors: D
authors: Yu
authors: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Gabriel N
authors: http://orcid.org/0000-0002-4873-4412
authors: GN
authors: Hortobagyi
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.|Department of Biotechnology, Asia University, Taichung 413, Taiwan.
authors: Mien-Chie
authors: MC
authors: Hung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism*; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007157:Immunologic Surveillance / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology*; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011799:Quinazolines; D044844:beta-Transducin Repeat-Containing Proteins; D004815:Epidermal Growth Factor; D000071679:Glycogen Synthase Kinase 3 beta; D000077156:Gefitinib