Prognostic stratification based on m5C regulators acts as a novel biomarker for immunotherapy in hepatocellular carcinoma

Ping Liu; Ziqing Zhu; Jiayao Ma; Le Wei; Ying Han; Edward Shen; Xiao Tan; Yihong Chen; Changjing Cai; Cao Guo; Yinghui Peng; Yan Gao; Yongting Liu; Qiaoqiao Huang; Le Gao; Yin Li; Zhaohui Jiang; Wantao Wu; Yihan Liu; Shan Zeng; Wei Li; Ziyang Feng; Hong Shen

doi:10.3389/fimmu.2022.951529

Prognostic stratification based on m⁵C regulators acts as a novel biomarker for immunotherapy in hepatocellular carcinoma

Front Immunol. 2022 Sep 9:13:951529. doi: 10.3389/fimmu.2022.951529. eCollection 2022.

Authors

Ping Liu^{1

2}, Ziqing Zhu^{1

2}, Jiayao Ma^{1

2}, Le Wei^{1

2}, Ying Han^{1

2}, Edward Shen³, Xiao Tan¹, Yihong Chen^{1

2}, Changjing Cai^{1

2}, Cao Guo^{1

2}, Yinghui Peng^{1

2}, Yan Gao^{1

2}, Yongting Liu^{1

2}, Qiaoqiao Huang^{1

2}, Le Gao^{1

2}, Yin Li^{1

2}, Zhaohui Jiang^{1

2}, Wantao Wu^{1

2}, Yihan Liu^{1

2}, Shan Zeng^{1

2

4}, Wei Li^{1

2}, Ziyang Feng^{1

2}, Hong Shen^{1

2

4}

Affiliations

¹ Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
² Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China.
³ Department of Life Science, McMaster University, Hamilton, ON, Canada.
⁴ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.

Abstract

Background: Immunotherapy is a promising anti-cancer strategy in hepatocellular carcinoma (HCC). However, a limited number of patients can benefit from it. There are currently no reliable biomarkers available to find the potential beneficiaries. Methylcytosine (m⁵C) is crucial in HCC, but its role in forecasting clinical responses to immunotherapy has not been fully clarified.

Methods: In this study, we analyzed 371 HCC patients from The Cancer Genome Atlas (TCGA) database and investigated the expression of 18 m⁵C regulators. We selected 6 differentially expressed genes (DEGs) to construct a prognostic risk model as well as 2 m⁵C-related diagnostic models.

Results: The 1-, 3-, and 5-year area under the curve (AUC) of m⁵C scores for the overall survival (OS) was 0.781/0.762/0.711, indicating the m⁵C score system had an ideal distinction of prognostic prediction for HCC. The survival analysis showed that patients with high-risk scores present a worse prognosis than the patients with low-risk scores (p< 0.0001). We got consistent results in 6 public cohorts and validated them in Xiangya real-world cohort by quantitative real-time PCR and immunohistochemical (IHC) assays. The high-m⁵C score group was predicted to be in an immune evasion state and showed low sensitivity to immunotherapy, but high sensitivity to chemotherapy and potential targeted drugs and agents, such as sepantronium bromide (YM-155), axitinib, vinblastine and docetaxel. Meanwhile, we also constructed two diagnostic models to distinguish HCC tumors from normal liver tissues or liver cirrhosis.

Conclusion: In conclusion, our study helps to early screen HCC patients and select patients who can benefit from immunotherapy. Step forwardly, for the less likely beneficiaries, this study provides them with new potential targeted drugs and agents for choice to improve their prognosis.

Keywords: HCC; biomarker; drug sensitivity; immunotherapy; m5C; precision medicine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Axitinib
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / therapy
Docetaxel
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic
Humans
Immunotherapy
Liver Neoplasms* / genetics
Liver Neoplasms* / therapy
Prognosis
Vinblastine

Substances

Biomarkers, Tumor
Docetaxel
Vinblastine
Axitinib