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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| Vydané v: | Gastroenterology (New York, N.Y. 1943) Ročník 156; číslo 6; s. 1849 |
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| Médium: | Journal Article |
| Jazyk: | English |
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United States
01.05.2019
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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.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. 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. |
| Author | Yamaguchi, Hirohito Li, Xiaoqiang Ding, Qingqing Hung, Mien-Chie Lai, Yun-Ju Li, Hui Guo, Lei Liu, Chunxiao Hsu, Jung-Mao Li, Chia-Wei Hsu, Jennifer L Xia, Weiya Sun, Xian Ye, Qinghai Lai, Chien-Chen Koller, Paul B Dong, Qiongzhu Du, Yi Liu, Shuang |
| 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; 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: 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 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; Institute of Molecular Biology, National Chung Hsing 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; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan – sequence: 13 givenname: Hirohito 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; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. Electronic address: mhung@mdanderson.org |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30711629$$D View this record in MEDLINE/PubMed |
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| Title | MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1 |
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