Molecular Signature and Immune Landscape of HCV-Associated Hepatocellular Carcinoma (HCC): Differences and Similarities with HBV-HCC

• Published in: Journal of hepatocellular carcinoma 2021-01, Vol.8, p.1399-1413
• Main Authors: De Battista, Davide, Zamboni, Fausto, Gerstein, Hannah, Sato, Shinya, Markowitz, Tovah E, Lack, Justin, Engle, Ronald E, Farci, Patrizia
• Format: Article
• Language: English
• Subjects: CD20 antigen; CD3 antigen; CD8 antigen; Cell activation; Cell cycle; Etiology; Gene expression; Genomes; Hepatitis; Hepatitis B; hepatitis b virus; Hepatitis C; hepatitis c virus; Hepatocellular carcinoma; immune landscape; Immunohistochemistry; Infiltration; Liver; Liver cancer; Lymphocytes T; Macrophages; Metastases; Microenvironments; molecular signature; Monocytes; Mortality; Original Research; Oxidative stress; Paraffin; Pathogenesis; rna-sequencing; Solid tumors; Statistical analysis; Transcription activation; Tumors; Viruses
• ISSN: 2253-5969; 2253-5969
• DOI: 10.2147/JHC.S325959

HCC is the third leading cause of cancer-related death worldwide, with chronic viral hepatitis accounting for more than 70% of the cases. Therapeutic options are limited and ineffective. The increasing use of immune-based therapies in solid tumors highlights the need to expand our knowledge on the immunologic microenvironment of HCC. Access to liver samples from 20 well-characterized patients with HCC associated with HCV (n = 9) or HBV (n = 11) gave us the opportunity to study the immunologic landscape in these tumors. For each patient, RNA-sequencing was performed on the tumor and surrounding nontumorous tissue. We found that both HCV- and HBV-HCC are associated with a predominance of downregulated genes (74% and 67%, respectively). Analysis of the immune landscape using a curated gene list showed 216 of 2481 (9%) immune genes in HCV-HCC and 164 of 2560 (6%) in HBV-HCC. However, only 8 immune genes (4%) were upregulated in HCV-HCC and 27 (16.5%) in HBV-HCC. HCV-HCC was characterized by an enrichment of downregulated genes related to T-cell activation and oxidative stress. The dramatic downregulation of immune genes related to T-cell activation in HCV-HCC prompted us to perform an extensive immunohistochemistry analysis on paraffin-embedded liver specimen. Interestingly, we found a significant reduction of immune-cell infiltration (CD3, CD8 and CD20 positive cells) within the tumor. Moreover, we observed that HCV-HCC is characterized by an enrichment of M2-like CD68-positive cells. These data are consistent with the dramatic downregulation of immune-cell infiltration seen in HCV-HCC. Conversely, HBV-HCC was characterized by upregulation of genes related to monocyte/macrophage activation and cell cycle control, and downregulation of genes involved in various cell metabolisms. This study demonstrates a distinctive molecular signature and immune landscape in HCC of different viral etiology, which could provide new insights into pathogenesis and lead to the development of novel immune-based therapies.