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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 3? (GSK3?) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by ?-TrCP. In-depth analysis of PD-L1 N192, N200 and N219 glycosylation suggests that glycosylation antagonizes GSK3? binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3? and ?-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3? 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.

SUBMITTER: Li CW

PROVIDER: S-EPMC5013604 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Li Chia-Wei CW Lim Seung-Oe SO Xia Weiya W Lee Heng-Huan HH Chan Li-Chuan LC Kuo Chu-Wei CW Khoo Kay-Hooi KH Chang Shih-Shin SS Cha Jong-Ho JH Kim Taewan T Hsu Jennifer L JL Wu Yun Y Hsu Jung-Mao JM Yamaguchi Hirohito H Ding Qingqing Q Wang Yan Y Yao Jun J Lee Cheng-Chung CC Wu Hsing-Ju HJ Sahin Aysegul A AA Allison James P JP Yu Dihua D Hortobagyi Gabriel N GN Hung Mien-Chie MC

Nature communications 20160830

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 ...[more]

PMID: 27572267

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Project description:A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients.Blood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-?) and interleukin-2 (IL-2) production were quantitated by flow cytometry.Lymphocytes from septic patients produced decreased IFN-? and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-?, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-? and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01).In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.

Dataset Information

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

Publications

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

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