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Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification
Open accessAbstract
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.
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“Several gene signatures capturing the inflamed components of the TME have been associated with a favourable response to ICIs69,72,78–81, but none has been clinically validated thus far.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [78]
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“Overall, patients with inflamed HCCs tend to have a favourable prognosis and are the most likely to have improved outcomes when receiving ICIs owing to the presence of responsive immune cells72,78.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [78]
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“Molecular classifications have identified classes of hepatocellular carcinoma associated with ICI responsiveness (inflamed class) and ICI resistance (excluded class).26”
From Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis (2024) · cites this paper as [26]
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“Inflamed tumours constitute ~30% of HCCs and exhibit extensive immune cell infiltration and immune activity, detected as increased expression of immune checkpoints (such as PD-1 or its ligand PD-L1), activation of IFN signalling and a low burden of large chromosomal alterations70,71,78.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [78]
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Metadata
- Authors
- Montironi, C., Castet, F., Haber, P. K., Pinyol, R., Torres-Martin, M., Torrens, L., Mesropian, A., Wang, H., Puigvehi, M., Maeda, M., Leow, W. Q., Harrod, E., Taik, P., Chinburen, J., Taivanbaatar, E., Chinbold, E., Solé Arqués, M., Donovan, M., Thung, S., Neely, J., Mazzaferro, V., Anderson, J., Roayaie, S., Schwartz, M., Villanueva, A., Friedman, S. L., Uzilov, A., Sia, D., & Llovet, J. M.
- Affiliations
- Hospital Clínic de Barcelona (ES)
- Tisch Cancer Institute (US)
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
- Sema4 (United States) (US)
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Singapore General Hospital (SG)
- Royal Surrey County Hospital (GB)
- Hepato-Pancreatico-Biliary Surgery Department, National Cancer Center, Ulaanbaatar, Mongolia
- Bristol-Myers Squibb (United States) (US)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- White Plains Hospital (US)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Llovet, Josep M
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2022-02-23
- Volume
- 72
- Issue
- 1
- Pages
- 129-140
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC9395551
- OpenAlex
- W4213062169
- Cited by
- 253
- References
- 49
- Citations by year
- 2026: 48 · 2025: 52 · 2024: 66 · 2023: 67 · 2022: 19
- FWCI
- 21.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Gut (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Funders
- Dr. Franklin M. Klion Young Scientist Research Award (N/A)
- Generalitat de Catalunya (PERIS (SLT017/20/000206))
- National Cancer Institute (P30-CA196521)
- PhD Scientist Innovative Research Award (N/A)
- Instituto de Salud Carlos III (Rio Hortega grant (CM19/00039))
- Samuel Waxman Cancer Research Foundation (N/A)
- Acadèmia de Ciències Mèdiques i de la Salut de Catalunya i de Balears (N/A)
- Cancer Research UK (HUNTER, Ref. C9380/A26813)
- Associazione Italiana per la Ricerca sul Cancro (HUNTER, Ref. C9380/A26813)
- U.S. Department of Defense (CA150272P3)
- Tisch Cancer Institute (N/A)
- Horizon 2020 Framework Programme (HEPCAR, Ref. 667273-2)
- Deutsche Forschungsgemeinschaft (DFG: HA 8754/1-1)
- Fundación Científica Asociación Española Contra el Cáncer (CLJUN20007CAST, HUNTER, Ref. C9380/A26813)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (SAF2016-76390)
- Agència de Gestió d’Ajuts Universitaris i de Recerca (SGR-1358)
- Bristol-Myers Squibb (N/A)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK128289, R01-128289, R01-56621)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- hepatocellular carcinoma, immune evasion, immunotherapy response prediction, interferon signaling, T cell receptor repertoire, TP53 mutation, CTNNB1 mutation, Wnt/β-catenin signaling, promoter hypomethylation, liquid biopsy, gene expression signatures, immune-related genes
- MeSH terms
- Carcinoma, Hepatocellular, Humans, Interferons, Liver Neoplasms, Mutation, DNA Methylation, Wnt Signaling Pathway
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