Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification

• Published in: Gut Vol. 72; no. 1; pp. 129 - 140
• Main Authors: Montironi, Carla, Castet, Florian, Haber, Philipp K, Pinyol, Roser, Torres-Martin, Miguel, Torrens, Laura, Mesropian, Agavni, Wang, Huan, Puigvehi, Marc, Maeda, Miho, Leow, Wei Qiang, Harrod, Elizabeth, Taik, Patricia, Chinburen, Jigjidsuren, Taivanbaatar, Erdenebileg, Chinbold, Enkhbold, Solé Arqués, Manel, Donovan, Michael, Thung, Swan, Neely, Jaclyn, Mazzaferro, Vincenzo, Anderson, Jeffrey, Roayaie, Sasan, Schwartz, Myron, Villanueva, Augusto, Friedman, Scott L, Uzilov, Andrew, Sia, Daniela, Llovet, Josep M
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.01.2023; BMJ Publishing Group LTD
• Subjects: Biomarkers; Biopsy; Cancer therapies; Carcinoma, Hepatocellular - pathology; Cytolytic activity; DNA Methylation; Gene amplification; Genomes; Genomics; Hepatitis B; Hepatitis C; Hepatocellular carcinoma; Hepatology; Humans; Immune response; Immune system; Immunofluorescence; Immunohistochemistry; Immunotherapy; Inflammation; Interferon; Interferons; Liver cancer; liver immunology; Liver Neoplasms - pathology; Lymphocytes T; molecular oncology; Mutation; p53 Protein; Signal transduction; T cell receptors; Tumors; Wnt protein; Wnt Signaling Pathway - genetics; molecular oncology; liver immunology; immune response; hepatocellular carcinoma; immunotherapy
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2021-325918

ObjectiveWe previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy.DesignWe performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients.ResultsOur integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in TP53 mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in CTNNB1 mutations (93% vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-βcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes.ConclusionWe have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC.