Molecular Signature and Immune Landscape of HCV-Associated Hepatocellular Carcinoma (HCC): Differences and Similarities with HBV-HCC
Davide De Battista,1 Fausto Zamboni,2 Hannah Gerstein,1 Shinya Sato,1 Tovah E Markowitz,3,4 Justin Lack,3,4 Ronald E Engle,1 Patrizia Farci1 1Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesd...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2021-11-01
|
| Series: | Journal of Hepatocellular Carcinoma |
| Subjects: | |
| Online Access: | https://www.dovepress.com/molecular-signature-and-immune-landscape-of-hcv-associated-hepatocellu-peer-reviewed-fulltext-article-JHC |
| _version_ | 1818824054754246656 |
|---|---|
| author | De Battista D Zamboni F Gerstein H Sato S Markowitz TE Lack J Engle RE Farci P |
| author_facet | De Battista D Zamboni F Gerstein H Sato S Markowitz TE Lack J Engle RE Farci P |
| author_sort | De Battista D |
| collection | DOAJ |
| description | Davide De Battista,1 Fausto Zamboni,2 Hannah Gerstein,1 Shinya Sato,1 Tovah E Markowitz,3,4 Justin Lack,3,4 Ronald E Engle,1 Patrizia Farci1 1Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA; 2Liver Transplantation Center, Azienda Ospedaliera Brotzu, Cagliari, Italy; 3NIAID Collaborative Bioinformatics Resource, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA; 4Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, MD, 21702, USACorrespondence: Patrizia FarciHepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USATel +1 240-669-5921Fax +1 301-402-0524Email pfarci@niaid.nih.govIntroduction: 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.Methods: 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.Results: 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.Conclusion: 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.Keywords: hepatocellular carcinoma, hepatitis C virus, hepatitis B virus, RNA-sequencing, molecular signature, immune landscape |
| first_indexed | 2024-12-18T23:49:47Z |
| format | Article |
| id | doaj.art-a7a87535b8604d668cd9da74863b658a |
| institution | Directory Open Access Journal |
| issn | 2253-5969 |
| language | English |
| last_indexed | 2024-12-18T23:49:47Z |
| publishDate | 2021-11-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Journal of Hepatocellular Carcinoma |
| spelling | doaj.art-a7a87535b8604d668cd9da74863b658a2022-12-21T20:47:02ZengDove Medical PressJournal of Hepatocellular Carcinoma2253-59692021-11-01Volume 81399141370767Molecular Signature and Immune Landscape of HCV-Associated Hepatocellular Carcinoma (HCC): Differences and Similarities with HBV-HCCDe Battista DZamboni FGerstein HSato SMarkowitz TELack JEngle REFarci PDavide De Battista,1 Fausto Zamboni,2 Hannah Gerstein,1 Shinya Sato,1 Tovah E Markowitz,3,4 Justin Lack,3,4 Ronald E Engle,1 Patrizia Farci1 1Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA; 2Liver Transplantation Center, Azienda Ospedaliera Brotzu, Cagliari, Italy; 3NIAID Collaborative Bioinformatics Resource, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA; 4Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, MD, 21702, USACorrespondence: Patrizia FarciHepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USATel +1 240-669-5921Fax +1 301-402-0524Email pfarci@niaid.nih.govIntroduction: 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.Methods: 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.Results: 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.Conclusion: 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.Keywords: hepatocellular carcinoma, hepatitis C virus, hepatitis B virus, RNA-sequencing, molecular signature, immune landscapehttps://www.dovepress.com/molecular-signature-and-immune-landscape-of-hcv-associated-hepatocellu-peer-reviewed-fulltext-article-JHChepatocellular carcinomahepatitis c virushepatitis b virusrna-sequencingmolecular signatureimmune landscape |
| spellingShingle | De Battista D Zamboni F Gerstein H Sato S Markowitz TE Lack J Engle RE Farci P Molecular Signature and Immune Landscape of HCV-Associated Hepatocellular Carcinoma (HCC): Differences and Similarities with HBV-HCC Journal of Hepatocellular Carcinoma hepatocellular carcinoma hepatitis c virus hepatitis b virus rna-sequencing molecular signature immune landscape |
| title | Molecular Signature and Immune Landscape of HCV-Associated Hepatocellular Carcinoma (HCC): Differences and Similarities with HBV-HCC |
| title_full | Molecular Signature and Immune Landscape of HCV-Associated Hepatocellular Carcinoma (HCC): Differences and Similarities with HBV-HCC |
| title_fullStr | Molecular Signature and Immune Landscape of HCV-Associated Hepatocellular Carcinoma (HCC): Differences and Similarities with HBV-HCC |
| title_full_unstemmed | Molecular Signature and Immune Landscape of HCV-Associated Hepatocellular Carcinoma (HCC): Differences and Similarities with HBV-HCC |
| title_short | Molecular Signature and Immune Landscape of HCV-Associated Hepatocellular Carcinoma (HCC): Differences and Similarities with HBV-HCC |
| title_sort | molecular signature and immune landscape of hcv associated hepatocellular carcinoma hcc differences and similarities with hbv hcc |
| topic | hepatocellular carcinoma hepatitis c virus hepatitis b virus rna-sequencing molecular signature immune landscape |
| url | https://www.dovepress.com/molecular-signature-and-immune-landscape-of-hcv-associated-hepatocellu-peer-reviewed-fulltext-article-JHC |
| work_keys_str_mv | AT debattistad molecularsignatureandimmunelandscapeofhcvassociatedhepatocellularcarcinomahccdifferencesandsimilaritieswithhbvhcc AT zambonif molecularsignatureandimmunelandscapeofhcvassociatedhepatocellularcarcinomahccdifferencesandsimilaritieswithhbvhcc AT gersteinh molecularsignatureandimmunelandscapeofhcvassociatedhepatocellularcarcinomahccdifferencesandsimilaritieswithhbvhcc AT satos molecularsignatureandimmunelandscapeofhcvassociatedhepatocellularcarcinomahccdifferencesandsimilaritieswithhbvhcc AT markowitzte molecularsignatureandimmunelandscapeofhcvassociatedhepatocellularcarcinomahccdifferencesandsimilaritieswithhbvhcc AT lackj molecularsignatureandimmunelandscapeofhcvassociatedhepatocellularcarcinomahccdifferencesandsimilaritieswithhbvhcc AT englere molecularsignatureandimmunelandscapeofhcvassociatedhepatocellularcarcinomahccdifferencesandsimilaritieswithhbvhcc AT farcip molecularsignatureandimmunelandscapeofhcvassociatedhepatocellularcarcinomahccdifferencesandsimilaritieswithhbvhcc |