Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1
Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin’s role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducin...
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| Published in | Molecular cell Vol. 71; no. 4; pp. 606 - 620.e7 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
16.08.2018
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin’s role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.
[Display omitted]
•Metformin enhances antitumor CTL immunity by blocking PD-L1/PD-1 axis•Metformin-activated AMPK directly binds to and phosphorylates PD-L1 at S195•Abnormal PD-L1 glycosylation induced by pS195 leads to PD-L1 degradation by ERAD•Combination therapy with metformin and anti-CTLA4 has a synergistic antitumor effect
Cha et al. elucidated a mechanism to show that metformin-activated AMPK phosphorylates PD-L1 at S195 to induce abnormal glycosylation and degrades PD-L1 through an ERAD pathway. This study suggests the potential to use metformin as an adjuvant with various non-PD-L1/PD-1-targeting immune therapies. |
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| AbstractList | Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin’s role in cancer immunity are not fully understood. Here we show metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.
Cha et al.
elucidated a mechanism that metformin-activated AMPK phosphorylates PD-L1 at S195 to induce abnormal glycosylation and degrades PD-L1 through ERAD pathway. This study suggests the potential to use metformin as an adjuvant with various non-PD-L1/PD-1 targeting immune therapies. Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin’s role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy. [Display omitted] •Metformin enhances antitumor CTL immunity by blocking PD-L1/PD-1 axis•Metformin-activated AMPK directly binds to and phosphorylates PD-L1 at S195•Abnormal PD-L1 glycosylation induced by pS195 leads to PD-L1 degradation by ERAD•Combination therapy with metformin and anti-CTLA4 has a synergistic antitumor effect Cha et al. elucidated a mechanism to show that metformin-activated AMPK phosphorylates PD-L1 at S195 to induce abnormal glycosylation and degrades PD-L1 through an ERAD pathway. This study suggests the potential to use metformin as an adjuvant with various non-PD-L1/PD-1-targeting immune therapies. Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy. Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy. |
| Author | Lim, Seung-Oe McCoy, Aaron M. Khoo, Kay-Hooi Hadad, Sirwan Cai, Shirong Thompson, Alastair M. Hung, Mien-Chie Chan, Li-Chuan Litton, Jennifer K. Li, Chia-Wei Kim, Taewan Kuo, Chu-Wei Xia, Weiya Cha, Jong-Ho Symmans, William F. Mittendorf, Elizabeth A. Chang, Shih-Shin Yang, Wen-Hao Moulder, Stacy L. Piwnica-Worms, Helen Tu, Yizheng Lee, Heng-Huan Chen, Chung-Hsuan Wei, Yongkun Hsu, Jennifer L. Wang, Hung-Ling Purdie, Colin A. Chang, Wei-Chao |
| AuthorAffiliation | 3 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 7 Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX 77030, USA 8 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan 11 Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan 9 Department of Biotechnology, Asia University, Taichung 413, Taiwan 10 Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan 13 Department of Pathology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK 6 Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 4 Department of Breast Surgical oncology, The University of Texas MD Anderson Cancer Center, Houston, |
| AuthorAffiliation_xml | – name: 6 Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea – name: 10 Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan – name: 11 Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan – name: 15 Lead Contact – name: 7 Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX 77030, USA – name: 2 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – name: 5 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – name: 9 Department of Biotechnology, Asia University, Taichung 413, Taiwan – name: 13 Department of Pathology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK – name: 12 Department of Surgery, University of Sheffield, Western Bank, Sheffield S10 2TN, UK – name: 14 These authors contributed equally – name: 4 Department of Breast Surgical oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – name: 8 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan – name: 3 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – name: 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA |
| Author_xml | – sequence: 1 givenname: Jong-Ho surname: Cha fullname: Cha, Jong-Ho organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 2 givenname: Wen-Hao surname: Yang fullname: Yang, Wen-Hao organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 3 givenname: Weiya surname: Xia fullname: Xia, Weiya organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 4 givenname: Yongkun surname: Wei fullname: Wei, Yongkun organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 5 givenname: Li-Chuan surname: Chan fullname: Chan, Li-Chuan organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 6 givenname: Seung-Oe surname: Lim fullname: Lim, Seung-Oe organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 7 givenname: Chia-Wei surname: Li fullname: Li, Chia-Wei organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 8 givenname: Taewan surname: Kim fullname: Kim, Taewan organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 9 givenname: Shih-Shin surname: Chang fullname: Chang, Shih-Shin organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 10 givenname: Heng-Huan surname: Lee fullname: Lee, Heng-Huan organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 11 givenname: Jennifer L. surname: Hsu fullname: Hsu, Jennifer L. organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 12 givenname: Hung-Ling surname: Wang fullname: Wang, Hung-Ling organization: Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan – sequence: 13 givenname: Chu-Wei surname: Kuo fullname: Kuo, Chu-Wei organization: Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan – sequence: 14 givenname: Wei-Chao surname: Chang fullname: Chang, Wei-Chao organization: Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan – sequence: 15 givenname: Sirwan surname: Hadad fullname: Hadad, Sirwan organization: Department of Surgery, University of Sheffield, Western Bank, Sheffield S10 2TN, UK – sequence: 16 givenname: Colin A. surname: Purdie fullname: Purdie, Colin A. organization: Department of Pathology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK – sequence: 17 givenname: Aaron M. surname: McCoy fullname: McCoy, Aaron M. organization: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 18 givenname: Shirong surname: Cai fullname: Cai, Shirong organization: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 19 givenname: Yizheng surname: Tu fullname: Tu, Yizheng organization: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 20 givenname: Jennifer K. surname: Litton fullname: Litton, Jennifer K. organization: Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 21 givenname: Elizabeth A. surname: Mittendorf fullname: Mittendorf, Elizabeth A. organization: Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 22 givenname: Stacy L. surname: Moulder fullname: Moulder, Stacy L. organization: Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 23 givenname: William F. surname: Symmans fullname: Symmans, William F. organization: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 24 givenname: Alastair M. surname: Thompson fullname: Thompson, Alastair M. organization: Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 25 givenname: Helen surname: Piwnica-Worms fullname: Piwnica-Worms, Helen organization: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 26 givenname: Chung-Hsuan surname: Chen fullname: Chen, Chung-Hsuan organization: Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan – sequence: 27 givenname: Kay-Hooi surname: Khoo fullname: Khoo, Kay-Hooi organization: Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan – sequence: 28 givenname: Mien-Chie surname: Hung fullname: Hung, Mien-Chie email: mhung@mdanderson.org organization: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30118680$$D View this record in MEDLINE/PubMed |
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| Keywords | ERAD ER accumulation cancer immunotherapy PD-L1 metformin glycosylation immune checkpoint blockade |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 J.-H.C. and W.-H.Y. designed and performed the experiments, analyzed data, and wrote the manuscript; W.X., Y.W., L.-C.C, S.-O.L., C.-W.L., T.W.K., S.-S.C. and H.-H. L performed experiments and analyzed data; J.L.H. provided scientific input and wrote the manuscript; H.-L.W produced and characterized the PD-L1/S195-p antibody; C.-W. K and K.-H. K performed LC-MS/MS for glycan structure and analyzed data; W.-C.C. and C.-H. C. supported MS/IP and analyzed data; S.H., C.A.P., and A.M.T. provided metformin-treated human breast tumor samples; A.M.M., S.C., Y.T., and H.P.-W. provided breast cancer PDX model; S L. M., W. F. S., J.K.L. and E.A.M. contributed human breast tumor tissues to establish PDX model; M.-C.H. supervised the entire project, designed the experiments, analyzed data, and wrote the manuscript. Author Contributions |
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| Title | Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1 |
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