Purpose: The role of RNA N6-methyladenosine (m⁶A) modification in the progression of multiple tumours and the tumour microenvironment (TME) has been progressively demonstrated and promises a new direction for tumour therapy. However, there have been no reports on systematic analyses of RNA m⁶A modification in TME in non-small cell lung cancer (NSCLC).
Patients and Methods: In this study, we used unsupervised cluster analysis to identify three m⁶A modification patterns of 28 m⁶A regulators and three m⁶A gene signature subgroups of commonly differentially expressed genes (co-DEGs) in the three m⁶A modification patterns. Quantifying these subtypes using the ssGSEA and ESTIMATE algorithms to characterise the tumour immune microenvironment (TIME) in NSCLC. Based on the principal component analysis (PCA), we used co-DEGs to construct m⁶A scores to analyse the characteristics of m⁶A modifications in individual patients and assessed the practical clinical utility of m⁶A scores using a nomogram for survival prediction.
Results: A total of 28 m⁶A regulators in 1210 NSCLC samples were mainly enriched in RNA modification and metabolic biological processes. The three following m⁶A modification patterns were identified based on the role of the 28 m⁶A regulators in TME: immune inflammation, immune evasion and immune desert. The m⁶A scores calculated based on co-DEGs in these modification patterns were significantly positively correlated with immune infiltration and significantly negatively correlated with tumour mutational burden (TMB). Survival was significantly better in the high-m⁶A-score group than in the low-m⁶A-score group, and the m⁶A score could be used as an independent favourable prognostic factor. In addition, assessment of both immune checkpoint inhibitors (ICIs) and immunophenoscore (IPS) revealed a better immunotherapeutic effect in the high-m⁶A-score group.
Conclusion: The modification characteristics of 28 m⁶A regulators in the TIME of NSCLC were analysed from a comprehensive to an individual basis, which may facilitate the development of more effective clinical immunotherapeutic strategies.
Keywords: immunophenotype, immunotherapy, m⁶A modification, non-small cell lung cancer, tumour microenvironment