Published online Dec 27, 2022. doi: 10.4254/wjh.v14.i12.1997
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
Hepatocellular carcinoma (HCC) is a major cancer of the liver that constitutes around 90% of liver cancer cases. Although traditional therapeutic approaches, including surgery, chemotherapy, radiotherapy, and targeted therapy, are effective in improving the survival of HCC patients, the overall survival prognosis of HCC patients is generally unfavorable. More recently, immunotherapy, such as immune checkpoint blockade, has achieved success in the treatment of various cancers, including HCC. However, only a small proportion of cancer patients respond well to immunotherapies to date.
Certain predictive markers for cancer immunotherapy responses have been uncovered, e.g., PD-L1 expression, tumor mutation burden (TMB), and mismatch repair deficiency. In addition, the tumor immune microenvironment (TIME) plays an important role in immunotherapy responses. Overall, the “hot” tumors infiltrated by a substantial number of tumor-infiltrating lymphocytes (TILs) are more responsive to immunotherapies, compared to the “cold” tumors lacking TILs. Hence, an investigation of the TIME in HCC would aid in the prediction of immunotherapy responses.
Despite these previous studies, the discovery of immune-specific subtypes of hepatitis B virus-positive (HBV+) HCC is worth investigating, considering that HBV infection is a major cause of HCC.
In this study, to characterize the immunological landscape of HBV+ HCC, we identified its immune-specific subtypes by the unsupervised machine learning in transcriptomic data. Furthermore, we comprehensively compared the clinical and molecular features of these subtypes.
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.
Our immune-specific subtyping of HBV+ HCC may provide new biological insights as well as clinical implications for the management of this disease.
This study is interesting for several reasons. First, for the first time, we identified immune-specific subtypes of HBV+ 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.