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

Carla Montironi, Florian Castet, Philipp K. Haber, Roser Pinyol, Miguel Torres Martin, Laura Torrens, Huan Wang, Marc Puigvehi, Miho Maeda, Wei Qiang Leow, Elizabeth Harrod, Patricia Taik, Jigjidsuren Chinburen, Erdenebileg Taivanbaatar, Enkhbold Chinbold, Manel Solé Arqués, Michael Donovan, Swan Thung, Jaclyn Neely, Vincenzo MazzaferroJeffrey Anderson, Sasan Roayaie, Myron Schwartz, Augusto Villanueva, Scott L. Friedman, Andrew Uzilov, Daniela Sia, Josep M. Llovet

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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%, p0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-catenin 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.

Original languageEnglish
Pages (from-to)129-140
Number of pages12
JournalGut
Volume72
Issue number1
DOIs
StatePublished - 2023

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