Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Dec 27, 2022; 14(12): 1997-2011
Published online Dec 27, 2022. doi: 10.4254/wjh.v14.i12.1997
Immunological classification of hepatitis B virus-positive hepatocellular carcinoma by transcriptome analysis
Sheng-Wei Li, Li-Fan Han, Yin He, Xiao-Sheng Wang
Sheng-Wei Li, Li-Fan Han, Yin He, Xiao-Sheng Wang, Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu Province, China
Author contributions: Li SW contributed to software, validation, formal analysis, investigation, data curation, visualization, writing - review & editing; Han LF contributed to software, formal analysis, data curation; He Y contributed to data curation; Wang XS contributed to conceptualization, methodology, resources, investigation, writing - original draft, supervision, project administration, funding acquisition.
Institutional review board statement: Because we did not perform any human/animal experiments in this research, we could not provide the following file: Institutional review board approval form or document.
Institutional animal care and use committee statement: Because we did not perform any animal experiments in this research, we could not provide the file.
Conflict-of-interest statement: All the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Xiao-Sheng Wang, PhD, Associate Professor, Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Jiangning District, Nanjing 211198, Jiangsu Province, China.
Received: September 5, 2022
Peer-review started: September 5, 2022
First decision: September 30, 2022
Revised: October 12, 2022
Accepted: November 22, 2022
Article in press: November 22, 2022
Published online: December 27, 2022

Hepatitis B virus (HBV) infection is a major factor responsible for HBV+ hepatocellular carcinoma (HCC).


An immunological classification of HBV+ HCC may provide both biological insights and clinical implications for this disease.


Based on the enrichment of 23 immune signatures, we identified two immune-specific subtypes (Imm-H and Imm-L) of HBV+ HCC by unsupervised clustering. We showed that this subtyping method was reproducible and predictable by analyzing three different datasets.


Compared to Imm-L, Imm-H displayed stronger immunity, more stromal components, lower tumor purity, lower stemness and intratumor heterogeneity, lower-level copy number alterations, higher global methylation level, and better overall and disease-free survival prognosis. Besides immune-related pathways, stromal pathways (ECM receptor interaction, focal adhesion, and regulation of actin cytoskeleton) and neuro-related pathways (neuroactive ligand-receptor interaction, and prion diseases) were more highly enriched in Imm-H than in Imm-L. We identified nine proteins differentially expressed between Imm-H and Imm-L, of which MYH11, PDCD4, Dvl3, and Syk were upregulated in Imm-H, while PCNA, Acetyl-a-Tubulin-Lys40, ER-α_pS118, Cyclin E2, and β-Catenin were upregulated in Imm-L.


Our data suggest that “hot” tumors have a better prognosis than “cold” tumors in HBV+ HCC and that “hot” tumors respond better to immunotherapy.

Keywords: Hepatitis B virus, Hepatocellular carcinoma, Immunological classification, Transcriptomics, Tumor immunity, Cancer immunotherapy

Core Tip: First, for the first time, we identified immune-specific subtypes of hepatitis B virus (HBV) + hepatocellular carcinoma (HCC) based on immune signature scores and demonstrated that this new subtyping method was reproducible in three different datasets. Second, our subtyping method captures the comprehensive heterogeneity of HBV+ HCC in the tumor microenvironment, genomic integrity, protein expression profiles, DNA methylation profiles, tumor stemness, intratumor heterogeneity, and clinical outcomes. Third, our data suggest that it is copy number alterations but not tumor mutations responsible for the different immunity between the “hot” and “cold” tumor subtypes in HBV+ HCC. Finally, our identification of the immune-specific subtypes of HBV+ HCC may provide new insights into the tumor biology and identify the HBV+ HCC patients beneficial from immunotherapy.