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MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1 期刊论文

编号：

78445876-9cab-408c-9cd7-621ccf5b9534
作者：

Li, Hui^[1,2,3];Li, ChiaWei^[1];Li, Xiaoqiang^[4];Din, Qingqing^[5];Guo, Lei^[2,3];Liu, Shuang^[2,3];Liu, Chunxiao^[1];Lai, ChienChen^[6,7,8];Hsu, JungMao^[1];Dong, Qiongzhu(董琼珠)^[9]Xia, Weiya^[1];Hsu, Jennifer L.^[1,6,7];Yamaguchi, Hirohito^[1];Du, Yi^[1];Lai, YunJu^[10];Sun, Xian^[11];Koller, Paul B.^[1];Ye, Qinghai(叶青海)^[2,3]Hung, MienChie^[1,6,7];
语种：

英文
期刊：

GASTROENTEROLOGY ISSN：0016-5085 2019 年 156 卷 6 期 (1849 - +) ; MAY
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关键词：

Programmed Cell Death Ligand 1 Hepatocellular Carcinoma Tumor Necrosis Factor Receptor-Associated Factor 6 Glycogen Synthase Kinase 3
摘要：

BACKGROUND & AIMS: 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. METHODS: 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 3 beta (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. RESULTS: 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. CONCLUSIONS: 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.
推荐引用方式
GB/T 7714：

Li Hui,Li Chia-Wei,Li Xiaoqiang, et al. MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1 [J].GASTROENTEROLOGY,2019,156(6):1849-+.
APA：

Li Hui,Li Chia-Wei,Li Xiaoqiang,Din Qingqing,&Hung Mien-Chie.(2019).MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1 .GASTROENTEROLOGY,156(6):1849-+.
MLA：

Li Hui, et al. "MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1" .GASTROENTEROLOGY 156,6(2019):1849-+.
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