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Abstract

N6-methyladenosine (m6A) RNA modification is a reversible mechanism that regulates eukaryotic gene expression. Growing evidence has demonstrated an association between m6A modification and tumorigenesis and response to immunotherapy. However, the overall influence of m6A regulators on the tumor microenvironment and their effect on the response to immunotherapy in lung adenocarcinoma remains to be explored. Here, we comprehensively analyzed the m6A modification patterns of 936 lung adenocarcinoma samples based on 24 m6A regulators. First, we described the features of genetic variation in these m6A regulators. Many m6A regulators were aberrantly expressed in tumors and negatively correlated with most tumor-infiltrating immune cell types. Furthermore, we identified three m6A modification patterns using a consensus clustering method. m6A cluster B was preferentially associated with a favorable prognosis and enriched in metabolism-associated pathways. In contrast, m6A cluster A was associated with the worst prognosis and was enriched in the process of DNA repair. m6A cluster C was characterized by activation of the immune system and a higher stromal cell score. Surprisingly, patients who received radiotherapy had a better prognosis than patients without radiotherapy only in the m6A cluster C group. Subsequently, we constructed an m6A score model that qualified the m6A modification level of individual samples by using principal component analysis algorithms. Patients with high m6A score were characterized by enhanced immune cell infiltration and prolonged survival time, and were associated with lower tumor mutation burden and PD-1/CTLA4 expression. The combination of the m6A score and tumor mutation burden could accurately predict the prognosis of patients with lung adenocarcinoma. Furthermore, patients with high m6A score exhibited greater prognostic benefits from radiotherapy and immunotherapy. This study demonstrates that m6A modification is significantly associated with tumor microenvironment diversity and prognosis. A comprehensive evaluation of m6A modification patterns in single tumors will expand our understanding of the tumor immune landscape. In addition, our m6A score model demonstrated that the level of immune cell infiltration plays a significant role in cancer immunotherapy and provides a basis to increase the efficiency of current immune therapies and promote the clinical success of immunotherapy.