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

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.

m6A Methylation Patterns and Tumor Microenvironment Infiltration Characterization in Clear-Cell Renal Cell Carcinoma

“…When the m6A score we constructed was applied to other types of cancers, it represented poor survival accompanied by a high m6A score, which indicates that the m6A score may also reflect the aggressiveness and malignancy of cancers. Moreover, the association between immune checkpoint expression, burden of neoepitopes (TMB, MSI), and m6A score may illustrate that the phenotypes are affected by the m6A modification in tumors, contributing to uncontrolled immune disorders and dedifferentiation defined by loss of structure of origin, which was consistent with the findings of previous studies ( Zhang et al, 2020 ; Chong et al, 2021 ; Du et al, 2021 ; Li et al, 2021 ; Sun et al, 2021 ), indicating the robust and potential predictive value of the m6A score. However, this study has some limitations.…”

“…Accumulating evidence suggests that m6A modification plays pivotal roles in carcinogenesis, innate immunity, and anti-tumor immune response ( He et al, 2019 ; Gu et al, 2021 ; Uddin et al, 2021 ). Recently, the role of m6A modification patterns in TME infiltration characterizations has been comprehensively elucidated in other solid tumors ( Zhang et al, 2020 ; Chong et al, 2021 ; Du et al, 2021 ; Li et al, 2021 ; Sun et al, 2021 ). In this study, we explored the correlation between m6A modification and TME cell infiltration in ccRCC to enhance our apprehension of TME anti-tumor immune response and identify more effective immunotherapy strategies.…”

“…Han et al elucidated that YTHDF1 promotes the translational efficiency of lysosomal cathepsins in dendritic cells, while inhibition of YTHDF1 strikingly enhances the anti-tumor response of CD8 + T cells and immunotherapy efficacy ( Han et al, 2019 ). In addition, recent studies have identified the impressive role of m6A modification in reflecting TME status and predicting immunotherapy efficacy in gastric cancer (STAD), colon cancer (COAD), pancreatic cancer (PAAD), hepatocellular carcinoma (LIHC), and low-grade glioma (LGG) ( Zhang et al, 2020 ; Chong et al, 2021 ; Du et al, 2021 ; Li et al, 2021 ; Sun et al, 2021 ). Therefore, comprehensive recognition of the infiltration characteristics of TME mediated by a variety of m6A regulators will help strengthen our comprehension of TME and immunomodulatory effects.…”

N6-Methyladenosine in Cancer Immunotherapy: An Undervalued Therapeutic Target

“…Moreover, low m 6 A score, characterized by increased mutation burden and activation of immunity, indicates an inflamed TME phenotype and enhanced response to anti-PD-1/L1 immunotherapy in gastric cancer (GC) (65). In addition, m 6 A-related signature has been identified as biomarker for tumor immune phenotypes and anti-PD-1 immunotherapy treatment response in lung adenocarcinoma (LADC) (72,73), stomach adenocarcinomas (STADs) (74), Esophageal squamous cell carcinoma (ESCC) (75,76), Renal Papillary Cell Carcinoma (RPCC), Hepatocellular Carcinoma (HCC) (77,78). These statistic results together indicate that m 6 A modification may reflect TME status and predict immunotherapy efficacy in pan-cancers instead of limited to specific cancer types.…”

M5C modulator mediated methylation pattern and TME cell infiltration in bladder cancer

“…The immune-desert and immune-excluded phenotypes can be considered as non-in ammatory tumors, with little or no immune cell in ltration in the TME. The immunein ammatory phenotype was known as a thermo tumor and was characterized by extensive immune cell in ltrates in the TME [32][33][34][35]. Although a large number of immune cells also existed in the immuneexcluded phenotype, they only existed in the stroma around the tumor cell nest and failed to break through the tumor matrix to kill tumor cells or inhibit tumor cell proliferation.…”