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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study
Kaku Goto1,2, Dorcas A Annan3, Tomoko Morita3
1The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
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.
Insights
This study identifies vorinostat, a histone deacetylase inhibitor (HDACi), as a potential immunotherapy for hepatocellular carcinoma (HCC). HDACi treatment enhances natural killer (NK) cell activity against HCC by restoring MICA expression.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Pharmacotherapeutic options for hepatocellular carcinoma (HCC) are limited.
- A genome-wide association study (GWAS) identified the MHC class I polypeptide-related sequence A (MICA) gene as a susceptibility gene for hepatitis C virus-induced HCC.
Purpose of the Study:
- To explore HCC immunotherapy strategies based on GWAS findings.
- To identify drugs capable of restoring MICA expression in HCC cells.
Main Methods:
- Screening of an FDA-approved drug library to find compounds that restore MICA expression.
- Evaluating the effect of histone deacetylase inhibitors (HDACis) on MICA expression and natural killer (NK) cell cytotoxicity in vitro and in vivo.
- Utilizing metabolomics analysis to understand the underlying mechanisms.
Main Results:
- Vorinostat was identified as a potent agent that restores MICA expression in HCC cells.
- HDACi treatment significantly enhanced NK cell-mediated cytotoxicity against HCC cells, both in co-culture and in vivo.
- Inhibition of MICA sheddase further augmented NK cell anti-tumor activity.
- Metabolomics revealed HDACi-induced alterations in cellular energy and stress contributing to MICA induction and HCC inhibition.
Conclusions:
- HDACis, such as vorinostat, represent a promising strategy for HCC immunotherapy by enhancing NK cell activity.
- Restoring MICA expression and inhibiting MICA shedding are effective approaches for chemoimmunotherapy in HCC.
- These findings support the development of selective innate immunotherapy for HCC.
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