title: Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study.
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.
authors.affiliation: The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.|Japan Society for the Promotion of Science, Tokyo 102-8472, Japan.
authors.forename: Kaku
authors.initials: K
authors.lastname: Goto
authors.affiliation: Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.
authors.forename: Dorcas A
authors.initials: DA
authors.lastname: Annan
authors.affiliation: Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Morita
authors.affiliation: The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Li
authors.affiliation: The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Muroyama
authors.affiliation: The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ito
authors.affiliation: The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nakagawa
authors.affiliation: The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tanoue
authors.affiliation: Institute for Advanced Medical Research, Keio University Graduate School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Jinushi
authors.affiliation: The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kato
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D056945:Hep G2 Cells; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D055442:Metabolome / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology; D010447:Peptide Hydrolases / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C099187:MHC class I-related chain A; D009363:Neoplasm Proteins; D054852:Small Molecule Libraries; D000077337:Vorinostat; D010447:Peptide Hydrolases