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Hepatology
Original research
Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification
  1. Carla Montironi1,2,
  2. Florian Castet1,
  3. Philipp K Haber3,
  4. Roser Pinyol1,
  5. Miguel Torres-Martin1,
  6. Laura Torrens1,
  7. Agavni Mesropian1,
  8. Huan Wang4,
  9. Marc Puigvehi3,5,
  10. Miho Maeda3,
  11. Wei Qiang Leow3,6,
  12. Elizabeth Harrod3,7,8,
  13. Patricia Taik4,
  14. Jigjidsuren Chinburen9,
  15. Erdenebileg Taivanbaatar9,
  16. Enkhbold Chinbold9,
  17. Manel Solé Arqués1,
  18. Michael Donovan3,
  19. Swan Thung3,
  20. Jaclyn Neely10,
  21. Vincenzo Mazzaferro11,
  22. Jeffrey Anderson10,
  23. Sasan Roayaie12,
  24. Myron Schwartz3,
  25. Augusto Villanueva3,
  26. Scott L Friedman3,
  27. Andrew Uzilov4,13,
  28. Daniela Sia3,
  29. Josep M Llovet1,3,14
  1. 1Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
  2. 2Pathology Department & Molecular Biology CORE, Hospital Clinic de Barcelona, Barcelona, Spain
  3. 3Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  4. 4Sema4, Stamford, Connecticut, USA
  5. 5Hepatology Section, Gastroenterology Department, Consorci Parc de Salut Mar, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
  6. 6Department of Anatomical Pathology, Singapore General Hospital, Singapore
  7. 7Royal Surrey County Hospital, Guildford, UK
  8. 8University of Surrey, Guildford, UK
  9. 9Hepato-Pancreatico-Biliary Surgery Department, National Cancer Center, Ulaanbaatar, Mongolia
  10. 10Bristol-Myers Squibb, Princeton, New Jersey, USA
  11. 11Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy
  12. 12Department of Surgery, White Plains Hospital Center, White Plains, New York, USA
  13. 13Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  14. 14Institució Catalana De Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
  1. Correspondence to Dr Josep M Llovet, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Room 11-70A, 10029, New York, Tel.: +1-917-488-3207, New York, NY, USA; josep.llovet{at}mountsinai.org; Dr Daniela Sia, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai. 1425 Madison Avenue, Room 11-70A, 10029, New York, Tel.: +1-212-659-8315; Fax:+1-212-849-2574, New York, New York, USA; daniela.sia{at}mssm.edu

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.

  • hepatocellular carcinoma
  • molecular oncology
  • immunotherapy
  • liver immunology
  • immune response

Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. The RNAseq and Whole-exome sequencing data for the primary cohort have been deposited at the European Genome-Phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG) (Accession code EGAS00001005364). The TCRseq and any other relevant data can be obtained from the corresponding authors upon reasonable request. The data used for second cohort where the liquid-biopsy analysis was performed has been deposited at GEO with accession number GSE174570.

https://doi.org/10.1136/gutjnl-2021-325918

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    Data availability statement

    Data are available in a public, open access repository. Data are available on reasonable request. The RNAseq and Whole-exome sequencing data for the primary cohort have been deposited at the European Genome-Phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG) (Accession code EGAS00001005364). The TCRseq and any other relevant data can be obtained from the corresponding authors upon reasonable request. The data used for second cohort where the liquid-biopsy analysis was performed has been deposited at GEO with accession number GSE174570.

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    Footnotes

    • CM, FC and PKH are joint first authors.

    • Twitter @CMontironi, @LauraTorrensF

    • CM, FC and PKH contributed equally.

    • Correction notice This article has been corrected since it published Online First. The author's name, Laura Torrens, has been updated.

    • Contributors DS and JML designed the study. CM, FC, PH, MT-M, MP, DS and JML established and clinically annotated the cohort. CM, WQL, EH, MD and ST contributed to pathological characterisation of tumours and analysis of IHC/Multiplex immunofluorescence. MM, contributed to RNA and DNA isolation as well as to IHC profiling. CM, FC, PH, HW, AU, MP and DS contributed to data analysis. RP, LTF, AM, PT, JC, ET, EC, MS, JN, VM, JA, SR, MS, AV and SLF provided scientific input. CM, FC, DS and JML wrote the manuscript with contributions from all authors. DS and JML jointly supervised the work. JML is the author responsible for the overall content as the guarantor.

    • Funding This study was partially funded by a grant of Bristol-Myers Squibb to JML at Mount Sinai Liver Cancer Programme, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA. CM is supported by a Rio Hortega grant from Instituto de Salud Carlos III (ISCIII), Fondo Social Europeo, ID code (CM19/00039). FC is supported by a AECC Clínico Junior grant, ID code (CLJUN20007CAST). PKH is supported by the fellowship grant of the German Research Foundation (DFG: HA 8754/1–1). SLF is supported by grants from the NIDDK (R01-56621,R01-128289) and US Department of Defence (CA150272P3). DS is supported by the Tisch Cancer Institute, the Dr. Franklin M. Klion Young Scientist Research Award and the PhD Scientist Innovative Research Award. JML is supported by National Cancer Institute (P30-CA196521), NIDDK (R01 DK128289), US Department of Defence (CA150272P3), European Commission/Horizon 2020 Programme (HEPCAR, Ref. 6 67 273-2), Accelerator Award (CRUK, AECC, AIRC) (HUNTER, Ref. C9380/A26813), Samuel Waxman Cancer Research Foundation, Generalitat de Catalunya/AGAUR (SGR-1358), Plan Estratégico de Investigación e Innovación en Salud (PERIS) (SLT017/20/000206), and the Acadèmia de Ciències Mèdiques i de la Salut de Catalunya i de Balears, Ministerio de Economia y Competitividad (MINECO) proyectos de I+D+i PID2019-105378RB-100.

    • Competing interests JA and JN are staff scientists from Bristol-Myers Squibb. JML is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha Ltd and AstraZeneca. The remaining coauthors have nothing to disclose related to this manuscript.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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