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

Chia Wei Li; Seung Oe Lim; Weiya Xia; Heng Huan Lee; Li Chuan Chan; Chu Wei Kuo; Kay Hooi Khoo; Shih Shin Chang; Jong Ho Cha; Taewan Kim; Jennifer L. Hsu; Yun Wu; Jung Mao Hsu; Hirohito Yamaguchi; Qingqing Ding; Yan Wang; Jun Yao; Cheng Chung Lee; Hsing Ju Wu; Aysegul A. Sahin; James P. Allison; Dihua Yu; Gabriel N. Hortobagyi; Mien Chie Hung

doi:10.1038/ncomms12632

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

Chia Wei Li, Seung Oe Lim, Weiya Xia, Heng Huan Lee, Li Chuan Chan, Chu Wei Kuo, Kay Hooi Khoo, Shih Shin Chang, Jong Ho Cha, Taewan Kim, Jennifer L. Hsu, Yun Wu, Jung Mao Hsu, Hirohito Yamaguchi, Qingqing Ding, Yan Wang, Jun Yao, Cheng Chung Lee, Hsing Ju Wu, Aysegul A. SahinJames P. Allison, Dihua Yu, Gabriel N. Hortobagyi, Mien Chie Hung

Research output: Contribution to journal › Article › peer-review

686 Scopus citations

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.

Original language	English (US)
Article number	12632
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12632
State	Published - Aug 30 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Functional Genomics Core
Research Animal Support Facility
Small Animal Imaging Facility
Tissue Biospecimen and Pathology Resource
Cytogenetics and Cell Authentication Core

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10.1038/ncomms12632

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Li, C. W., Lim, S. O., Xia, W., Lee, H. H., Chan, L. C., Kuo, C. W., Khoo, K. H., Chang, S. S., Cha, J. H., Kim, T., Hsu, J. L., Wu, Y., Hsu, J. M., Yamaguchi, H., Ding, Q., Wang, Y., Yao, J., Lee, C. C., Wu, H. J., ... Hung, M. C. (2016). Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nature communications, 7, Article 12632. https://doi.org/10.1038/ncomms12632

Li, CW, Lim, SO, Xia, W, Lee, HH, Chan, LC, Kuo, CW, Khoo, KH, Chang, SS, Cha, JH, Kim, T, Hsu, JL, Wu, Y, Hsu, JM, Yamaguchi, H, Ding, Q, Wang, Y, Yao, J, Lee, CC, Wu, HJ, Sahin, AA , Allison, JP , Yu, D, Hortobagyi, GN & Hung, MC 2016, 'Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity', Nature communications, vol. 7, 12632. https://doi.org/10.1038/ncomms12632

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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.",

author = "Li, {Chia Wei} and Lim, {Seung Oe} and Weiya Xia and Lee, {Heng Huan} and Chan, {Li Chuan} and Kuo, {Chu Wei} and Khoo, {Kay Hooi} and Chang, {Shih Shin} and Cha, {Jong Ho} and Taewan Kim and Hsu, {Jennifer L.} and Yun Wu and Hsu, {Jung Mao} and Hirohito Yamaguchi and Qingqing Ding and Yan Wang and Jun Yao and Lee, {Cheng Chung} and Wu, {Hsing Ju} and Sahin, {Aysegul A.} and Allison, {James P.} and Dihua Yu and Hortobagyi, {Gabriel N.} and Hung, {Mien Chie}",

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doi = "10.1038/ncomms12632",

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AU - Li, Chia Wei

AU - Lim, Seung Oe

AU - Xia, Weiya

AU - Lee, Heng Huan

AU - Chan, Li Chuan

AU - Kuo, Chu Wei

AU - Khoo, Kay Hooi

AU - Chang, Shih Shin

AU - Cha, Jong Ho

AU - Kim, Taewan

AU - Hsu, Jennifer L.

AU - Wu, Yun

AU - Hsu, Jung Mao

AU - Yamaguchi, Hirohito

AU - Ding, Qingqing

AU - Wang, Yan

AU - Yao, Jun

AU - Lee, Cheng Chung

AU - Wu, Hsing Ju

AU - Sahin, Aysegul A.

AU - Allison, James P.

AU - Yu, Dihua

AU - Hortobagyi, Gabriel N.

AU - Hung, Mien Chie

PY - 2016/8/30

Y1 - 2016/8/30

N2 - 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.

AB - 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.

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

Abstract

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MD Anderson CCSG core facilities

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