Abstract
Pharmacotherapeutic options are limited for hepatocellular carcinoma (HCC). Recently, we identified the anti-tumor ligand MHC class I polypeptide-related sequence A (MICA) gene as a susceptibility gene for hepatitis C virus-induced HCC in a genome-wide association study (GWAS). To prove the concept of HCC immunotherapy based on the results of a GWAS, in the present study, we searched for drugs that could restore MICA expression. A screen of the FDA-approved drug library identified the anti-cancer agent vorinostat as the strongest hit, suggesting histone deacetylase inhibitors (HDACis) as potent candidates. Indeed, the HDACi-induced expression of MICA specific to HCC cells enhanced natural killer (NK) cell-mediated cytotoxicity in co-culture, which was further reinforced by treatment with an inhibitor of MICA sheddase. Similarly augmented anti-tumor activity of NK cells via NK group 2D was observed in vivo. Metabolomics analysis revealed HDACi-mediated alterations in energy supply and stresses for MICA induction and HCC inhibition, providing a mechanism for the chemoimmunotherapeutic actions. These data are indicative of promising strategies for selective HCC innate immunotherapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / immunology
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Carcinoma, Hepatocellular / pathology
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Carcinoma, Hepatocellular / therapy*
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Cell Line, Tumor
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Coculture Techniques
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Combined Modality Therapy
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Cytotoxicity, Immunologic / drug effects
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Gene Expression Regulation, Neoplastic*
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Genome-Wide Association Study
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Hep G2 Cells
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Histocompatibility Antigens Class I / genetics*
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Histocompatibility Antigens Class I / immunology
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Histone Deacetylase Inhibitors / pharmacology
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Humans
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Hydroxamic Acids / pharmacology*
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Immunotherapy / methods
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology
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Killer Cells, Natural / pathology
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Liver Neoplasms / genetics
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Liver Neoplasms / immunology
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Liver Neoplasms / pathology
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Liver Neoplasms / therapy*
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Metabolome / drug effects
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Metabolome / genetics
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Metabolome / immunology
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Mice
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Mice, Nude
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / immunology
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Peptide Hydrolases / pharmacology*
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Small Molecule Libraries / pharmacology
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T-Lymphocytes, Cytotoxic / drug effects
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / pathology
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Vorinostat
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Histocompatibility Antigens Class I
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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MHC class I-related chain A
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Neoplasm Proteins
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Small Molecule Libraries
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Vorinostat
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Peptide Hydrolases