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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification.

Carla Montironi1,2, Florian Castet1, Philipp K Haber3

  • 1Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.

Gut
|February 24, 2022
PubMed
Summary

This study defines new immunogenomic classes for hepatocellular carcinoma (HCC), identifying an "inflamed" class associated with immunotherapy response. These classifications aid in predicting patient outcomes and guiding treatment strategies for HCC.

Keywords:
hepatocellular carcinomaimmune responseimmunotherapyliver immunologymolecular oncology

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Area of Science:

  • Immunogenomics
  • Hepatocellular Carcinoma (HCC) Research
  • Tumor Microenvironment Analysis

Background:

  • Previous characterization of hepatocellular carcinoma (HCC) immune contexture identified an immune-specific class.
  • Further delineation is needed to understand features driving immunotherapy response or resistance in HCC.

Purpose of the Study:

  • To refine the immunogenomic classification of HCC.
  • To identify features correlating with response and resistance to immunotherapy.
  • To develop predictive biomarkers for HCC immunotherapy.

Main Methods:

  • Integrative analysis of RNA sequencing, whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence, and immunohistochemistry.
  • Utilized a cohort of 240 HCC patients and validated findings in 660 additional patients.
  • Developed a 20-gene signature and analyzed protein markers in liquid biopsies.

Main Results:

  • Defined three HCC classes: inflamed (37%), intermediate (enriched in TP53 mutations), and excluded (enriched in CTNNB1 mutations).
  • The inflamed class shows high interferon signaling, cytolytic activity, and diverse T-cell repertoire, with a 20-gene signature capturing ~90% of these tumors and predicting immunotherapy response.
  • Liquid biopsy proteins accurately identified the inflamed class (AUC 0.91). CTNNB1 mutations showed distinct patterns related to immune evasion.

Conclusions:

  • Characterized the immunogenomic contexture of HCC, defining inflamed and non-inflamed tumor subtypes.
  • Identified distinct CTNNB1 mutation patterns influencing immune evasion in HCC.
  • These immunogenomic features hold potential for predicting immunotherapy response in HCC patients.