ArticleGastroenterology2019
MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1.
Article in Gastroenterology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 122 papers.
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Who cites it
122 citing papers in PubMed, 186 citations in OpenAlex.
- MET-associated immune prognostic signature predicts survival and guides personalized therapy in glioma.Acta neuropathologica communications · 2026Article
- Advancing Systemic Treatment beyond First Line for Advanced Hepatocellular Carcinoma.Current oncology reports · 2026Review
- ETV4 Promotes Colorectal Cancer Progression by Reprogramming Asparagine Metabolism to Remodel the Stromal Microenvironment.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- MET Amplification in Gallbladder Cancer: a Case Report on a Precision Medicine Approach with Glumetinib and Envafolimab.Journal of gastrointestinal cancer · 2026Article
- Targeting SPAK suppresses progression and averts an immune exhaustive microenvironment in hepatocellular carcinoma.Nature communications · 2026Article
- Reply to correspondence 2 on "MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation".Clinical and molecular hepatology · 2026Article
- Butyrate enhances tumor immune evasion by increasing PD-L1 abundance.International journal of biological sciences · 2026Article
- The role of PD‑1/PD‑L1 axis in liver diseases.Clinical and experimental medicine · 2025Review
- LSD1 inhibition sensitizes anti-PD1 blockade immunotherapy by inhibiting the long-range attack of tumor-derived extracellular vesicles.Acta pharmaceutica Sinica. B · 2025Article
- Druggable genome CRISPR screening identifies the KEAP1/NRF2 axis as a mediator of PD-L1 expression.Communications biology · 2025Article
- From intracellular drivers to immune modulators: emerging paradigms in oncogenic pathway-directed immunotherapy optimization.Cell communication and signaling : CCS · 2025Review
- Antineuroblastoma Activity Evaluation and Mechanism of Novel PD-L1 Small Molecule Inhibitors through Immune and Non-Immune Pathways.ACS pharmacology & translational science · 2025Article
- Deciphering 17-β-hydroxysteroid dehydrogenase 4: from molecular insights to cancer therapeutics.Cancer cell international · 2025Review
- Parabacteroides distasonis promotes CXCL9 secretion of tumor-associated macrophages and enhances CD8BMC biotechnology · 2025Article
- ATF3 Within the Interferon Signaling Pathway: A Potential Biomarker for Predicting Pathological Response to Neoadjuvant Chemoimmunotherapy.Thoracic cancer · 2025Article
- Post-translational modifications of immune checkpoints: unlocking new potentials in cancer immunotherapy.Experimental hematology & oncology · 2025Review
- NSUN2/ALYREF axis-driven mCancer immunology, immunotherapy : CII · 2025Article
- Targeting HGF/c-MET signaling to regulate the tumor microenvironment: Implications for counteracting tumor immune evasion.Cell communication and signaling : CCS · 2025Review
- Unraveling the potential mechanism and prognostic value of pentose phosphate pathway in hepatocellular carcinoma: a comprehensive analysis integrating bulk transcriptomics and single-cell sequencing data.Functional & integrative genomics · 2025Article
- Exploring Autophagy-Related Gene Expression in Hepatocellular Carcinoma via TCGA, GEPIA2, and HPA Databases: Implications for Prognosis.Journal of hepatocellular carcinoma · 2025Article
62 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 7 institutions in 3 countries.
Funding
Abstract
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.
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.
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.
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.
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