Abstract
N(6)-methyladenosine (m(6)A) RNA modification is a reversible mechanism that regulates eukaryotic gene expression. Growing evidence has demonstrated an association between m(6)A modification and tumorigenesis and response to immunotherapy. However, the overall influence of m(6)A 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 m(6)A modification patterns of 936 lung adenocarcinoma samples based on 24 m(6)A regulators. First, we described the features of genetic variation in these m(6)A regulators. Many m(6)A regulators were aberrantly expressed in tumors and negatively correlated with most tumor-infiltrating immune cell types. Furthermore, we identified three m(6)A modification patterns using a consensus clustering method. m(6)A cluster B was preferentially associated with a favorable prognosis and enriched in metabolism-associated pathways. In contrast, m(6)A cluster A was associated with the worst prognosis and was enriched in the process of DNA repair. m(6)A 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 m(6)A cluster C group. Subsequently, we constructed an m(6)A score model that qualified the m(6)A modification level of individual samples by using principal component analysis algorithms. Patients with high m(6)A 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 m(6)A score and tumor mutation burden could accurately predict the prognosis of patients with lung adenocarcinoma. Furthermore, patients with high m(6)A score exhibited greater prognostic benefits from radiotherapy and immunotherapy. This study demonstrates that m(6)A modification is significantly associated with tumor microenvironment diversity and prognosis. A comprehensive evaluation of m(6)A modification patterns in single tumors will expand our understanding of the tumor immune landscape. In addition, our m(6)A 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.