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Novel genetic and immunological classification of hepatocellular carcinoma for the subtype-specific precision immunotherapy
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Shinji Tanaka1,2,
Shuichi Watanabe1,2,
Minoru Tanabe2 |
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1Department of Molecular Oncology, Tokyo Medical and Dental University, 2Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University |
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| The immune checkpoint inhibitor trial CheckMate040/nivolumab revealed the objective response rate (ORR) was 20% in patients with hepatocellular carcinoma (HCC). ORR was 19% of patients with low PD-L1 expression (<1%), indicating PD-L1 is insufficient for the biomarker. To identify the precise subtyping specific for molecular and immunotherapy, we identified hypermutator and immunological HCC subtypes using genome-editing technology and genome-scale analyses (J Hepatol 2017, Ann Gastroenterol Surg 2018, Am J Pathol 2018, EBioMedicine 2019). Whole genome sequencing has indicated ARID2-mutated HCC as the poorest prognosis subtype. Our CRISPR/Cas9 study revealed ARID2 deficiency attenuated DNA repair without XPG accumulation at DNA damage sites, leading to the hypermutator phenotype of HCC. In addition, comprehensive molecular evaluation of HCC by multi-platform analyses defined three major subtypes: (1) stem cell-like TP53-muated tumors with chromosomal instability and Treg-enrichment; (2) CTNNB1-mutated tumors displaying immunological ignorance (cold tumors); and (3) metabolic syndrome-associated tumors, which included an immunogenic subgroup characterized by enriched CD8+ T-cell infiltration (hot tumors). Although genomic and epigenomic analyses explicitly distinguished between HCC with intrahepatic metastasis (IM) and multi-centric HCC (MC), the phenotypic similarity between the primary and recurrent tumors was not correlated to the IM/MC origin, but to the classification per se. Identification of these HCC subtypes provides further insights into patient stratification and opportunities for therapeutic development. |
Index Term 1: hepatocellular carcinoma
Index Term 2: immunotherapy
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