m6A Regulator-Associated Modification Patterns and Immune Infiltration of the Tumor Microenvironment in Hepatocarcinoma

Jianhao Li; Weiwei Wang; Yubing Zhou; Liwen Liu; Guizhen Zhang; Kelei Guan; Xichun Cui; Xin Liu; Maoxin Huang; Guangying Cui; Ranran Sun

doi:10.3389/fcell.2021.687756

m6A Regulator-Associated Modification Patterns and Immune Infiltration of the Tumor Microenvironment in Hepatocarcinoma

Front Cell Dev Biol. 2021 Jul 2:9:687756. doi: 10.3389/fcell.2021.687756. eCollection 2021.

Authors

Jianhao Li^{1

2}, Weiwei Wang³, Yubing Zhou^{2

4}, Liwen Liu^{1

2}, Guizhen Zhang^{1

2}, Kelei Guan⁴, Xichun Cui², Xin Liu^{1

2}, Maoxin Huang⁵, Guangying Cui^{1

2}, Ranran Sun^{1

2}

Affiliations

¹ Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
³ Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁴ Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁵ Department of Dermatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Abstract

Background: Immunotherapy elicits durable responses in many tumors. Nevertheless, the positive response to immunotherapy always depends on the dynamic interactions between the tumor cells and infiltrating lymphocytes in the tumor microenvironment (TME). Currently, the application of immunotherapy in hepatocellular carcinoma (HCC) has achieved limited success. The ectopic modification of N6-methyladenosine (m6A) is a common feature in multiple tumors. However, the relationship between m6A modification with HCC clinical features, prognosis, immune cell infiltration, and immunotherapy efficacy remains unclear. Materials and Methods: Here, we comprehensively evaluated m6A modification clusters based on 22 m6A regulators and systematically explored the relationship between m6A modification with tumor progression, prognosis, and immune cell infiltration characteristics. The m6Ascore was calculated by principal component analysis to quantify the m6A modifications of individual patients. Key regulators involved in immunoregulation in HCC were identified using immunohistochemistry and immunofluorescence. Results: Three distinct m6A modification clusters were identified. The m6A clusters were significantly associated with clinical features, prognosis, and immune cell infiltration. The three clusters were highly consistent with the three tumor immune phenotypes, i.e., immune-excluded, immune-inflamed, and immune-desert. Comprehensive bioinformatics analysis revealed that high m6Ascore was closely associated with tumor progression, poor prognosis, and immunotherapy non-response. m6A regulators were dysregulated in HCC tissues. Hence, they play a role as predictors of poor prognosis. Tissue microarray demonstrated that overexpressed YTHDF1 was associated with low CD3⁺ and CD8⁺ T cell infiltration in HCC. Conclusion: Our findings demonstrate that m6A modification patterns play a crucial role in the tumor immune microenvironment and the prognosis of HCC. High YTHDF1 expression is closely associated with low CD3⁺ and CD8⁺ T cell infiltration in HCC.

Keywords: N6-methyladenosine; hepatocellular carcinoma; immune infiltration; prognosis; tumor microenvironment.