Integrative Analysis of m6A RNA Methylation Regulators and the Tumor Immune Microenvironment in Non-Small-Cell Lung Cancer

Abstract

Background: Non-small-cell lung cancer (NSCLC) is a major component of lung cancer and is significantly correlated with poor prognosis. N6-methyladenosine (m6A) RNA methylation is closely related to the occurrence, progression, and prognosis of cancer. The potential biological functions and mechanisms of m6A RNA methylation in the immune microenvironment are still unclear.

Methods: We assessed m6A RNA methylation modification patterns in 1326 NSCLC patient samples based on 20 m6A regulators, linking these clusters to the tumor microenvironment and immune cell infiltration. The m6Ascore was created to quantify the m6A modification patterns of individual tumors. We then assessed the value of NSCLC patients in terms of clinical prognosis and immunotherapy response.

Results: According to different mRNA expression levels, two different m6A clusters were identified. m6A aggregation was significantly associated with clinical prognostic characteristics, the tumor microenvironment, and immune-related biological processes. Fifteen differential genes were screened based on these two m6A clusters, and to further investigate the mechanisms of action of these differential genes, they were subjected to unsupervised clustering analysis, which classified them into four different genomic isoforms. Prognostic analysis indicated that the survival advantage of the m6A gene cluster A modification mode was significantly prominent. We continued to construct the m6Ascore, which was used as a scoring tool to evaluate tumor typing, immunity, and prognosis. Patients with a low m6Ascore showed a significant survival advantage, and the group with a low m6Ascore had a better prognosis predicted by immunotherapy. The anti-PD-1/L1 immunotherapy cohort showed that a lower m6Ascore was associated with higher efficacy of immunotherapy.

Conclusions: The results suggest that m6A RNA methylation regulators make an important difference in the tumor immune microenvironment of patients with NSCLC. m6A gene characterization and the construction of the m6Ascore provide us with a richer understanding of m6A RNA methylation modification patterns in NSCLC patients and help to predict clinical prognosis and immunotherapeutic response.