MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1
Inhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice. We tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell li...
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| Published in | Gastroenterology (New York, N.Y. 1943) Vol. 156; no. 6; pp. 1849 - 1861.e13 |
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| Main Authors | , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.05.2019
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Inhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice.
We tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3β (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry.
Exposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B.
In studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice. |
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| AbstractList | Inhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice.
We tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3β (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry.
Exposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B.
In studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice. Inhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice.BACKGROUND & AIMSInhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice.We tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3β (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry.METHODSWe tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3β (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry.Exposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B.RESULTSExposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B.In studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice.CONCLUSIONSIn studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice. |
| Author | Yamaguchi, Hirohito Koller, Paul B. Li, Xiaoqiang Ding, Qingqing Hung, Mien-Chie Lai, Yun-Ju Li, Hui Guo, Lei Liu, Chunxiao Hsu, Jung-Mao Hsu, Jennifer L. Li, Chia-Wei Xia, Weiya Sun, Xian Ye, Qinghai Lai, Chien-Chen Dong, Qiongzhu Du, Yi Liu, Shuang |
| AuthorAffiliation | 9 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China 8 Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 5 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan 7 Institutes of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China 4 Department of Pathology, University of Kansas Medical Center, Kansas City, Kansas 6 Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 3 Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China 2 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasi |
| AuthorAffiliation_xml | – name: 6 Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan – name: 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – name: 3 Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China – name: 8 Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas – name: 5 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan – name: 2 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People’s Republic of China – name: 9 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China – name: 7 Institutes of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China – name: 4 Department of Pathology, University of Kansas Medical Center, Kansas City, Kansas |
| Author_xml | – sequence: 1 givenname: Hui surname: Li fullname: Li, Hui organization: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 2 givenname: Chia-Wei surname: Li fullname: Li, Chia-Wei organization: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 3 givenname: Xiaoqiang orcidid: 0000-0002-9692-1458 surname: Li fullname: Li, Xiaoqiang organization: Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China – sequence: 4 givenname: Qingqing surname: Ding fullname: Ding, Qingqing organization: Department of Pathology, University of Kansas Medical Center, Kansas City, Kansas – sequence: 5 givenname: Lei surname: Guo fullname: Guo, Lei organization: Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People’s Republic of China – sequence: 6 givenname: Shuang surname: Liu fullname: Liu, Shuang organization: Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People’s Republic of China – sequence: 7 givenname: Chunxiao surname: Liu fullname: Liu, Chunxiao organization: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 8 givenname: Chien-Chen surname: Lai fullname: Lai, Chien-Chen organization: Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan – sequence: 9 givenname: Jung-Mao surname: Hsu fullname: Hsu, Jung-Mao organization: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 10 givenname: Qiongzhu surname: Dong fullname: Dong, Qiongzhu organization: Institutes of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China – sequence: 11 givenname: Weiya surname: Xia fullname: Xia, Weiya organization: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 12 givenname: Jennifer L. surname: Hsu fullname: Hsu, Jennifer L. organization: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 13 givenname: Hirohito orcidid: 0000-0003-0425-916X surname: Yamaguchi fullname: Yamaguchi, Hirohito organization: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 14 givenname: Yi surname: Du fullname: Du, Yi organization: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 15 givenname: Yun-Ju surname: Lai fullname: Lai, Yun-Ju organization: Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas – sequence: 16 givenname: Xian surname: Sun fullname: Sun, Xian organization: Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China – sequence: 17 givenname: Paul B. surname: Koller fullname: Koller, Paul B. organization: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 18 givenname: Qinghai surname: Ye fullname: Ye, Qinghai organization: Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People’s Republic of China – sequence: 19 givenname: Mien-Chie surname: Hung fullname: Hung, Mien-Chie email: mhung@mdanderson.org organization: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30711629$$D View this record in MEDLINE/PubMed |
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| Copyright | 2019 AGA Institute Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved. |
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| ISSN | 0016-5085 1528-0012 |
| IngestDate | Thu Aug 21 18:10:17 EDT 2025 Fri Jul 11 11:34:42 EDT 2025 Mon Jul 21 06:07:30 EDT 2025 Thu Apr 24 23:11:17 EDT 2025 Tue Jul 01 03:30:58 EDT 2025 Fri Feb 23 02:34:20 EST 2024 Tue Aug 26 16:40:42 EDT 2025 |
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| Issue | 6 |
| Keywords | GSK3B Y56F Glycogen Synthase Kinase 3 HCC Tumor Necrosis Factor Receptor-Associated Factor 6 p shRNA TRAF6 Y56 PD1 PDL1 WT Programmed Cell Death Ligand 1 Hepatocellular Carcinoma |
| Language | English |
| License | Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors share co-first authorship. Author contributions: Hui Li and Chia-Wei Li designed and performed the experiments, analyzed data, and wrote the manuscript. Xiaoqiang Li, Qingqing Ding, Shuang Liu, Lei Guo, Chunxiao Liu, Chien-Chen Lai, Jung-Mao Hsu, Yun-Ju Lai, Xian Sun, Paul B. Koller, and Weiya Xia performed experiments and analyzed data. Qinghai Ye provided patient tissue samples. Qiongzhu Dong, Hirohito Yamaguchi, and Yi Du provided scientific input and critical cells. Jennifer L. Hsu revised the manuscript. Mien-Chie Hung supervised the entire project, designed the experiments, analyzed data, and wrote the manuscript. Dr Yamaguchi’s present affiliation is: Cancer Research Center, Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar. |
| ORCID | 0000-0003-0425-916X 0000-0002-9692-1458 |
| OpenAccessLink | https://www.ncbi.nlm.nih.gov/pmc/articles/6904924 |
| PMID | 30711629 |
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| PublicationTitle | Gastroenterology (New York, N.Y. 1943) |
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| PublicationYear | 2019 |
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| SubjectTerms | Animals Antibodies, Monoclonal - therapeutic use Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use B7-H1 Antigen - antagonists & inhibitors B7-H1 Antigen - immunology B7-H1 Antigen - metabolism Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - enzymology Carcinoma, Hepatocellular - immunology Cell Line, Tumor Down-Regulation Glycogen Synthase Kinase 3 Glycogen Synthase Kinase 3 beta - metabolism Granzymes - metabolism Hepatocellular Carcinoma Imidazoles - pharmacology Imidazoles - therapeutic use Liver Neoplasms - drug therapy Liver Neoplasms - enzymology Liver Neoplasms - immunology Male Mice Phosphorylation Programmed Cell Death Ligand 1 Proto-Oncogene Proteins c-met - antagonists & inhibitors Proto-Oncogene Proteins c-met - metabolism Pyrrolidinones - pharmacology Pyrrolidinones - therapeutic use Quinolines - pharmacology Quinolines - therapeutic use TNF Receptor-Associated Factor 6 - immunology TNF Receptor-Associated Factor 6 - metabolism Triazines - pharmacology Triazines - therapeutic use Tumor Escape - drug effects Tumor Necrosis Factor Receptor-Associated Factor 6 Ubiquitination |
| Title | MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1 |
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