Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification. Issue 1 (23rd February 2022)

• Record Type: Journal Article
• 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
• Is Part Of: Gut. Volume 72:Issue 1(2023)
• Page Start: 129
• Page End: 140
• Publication Date: 2022-02-23
• Subjects: hepatocellular carcinoma -- molecular oncology -- immunotherapy -- liver immunology -- immune response; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2021-325918
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: We 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. Design: We 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. Results: Our 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. Conclusion: We 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.