Role of m6A modification in stromal and immune activation patterns together with response to ICI in melanoma

Abstract Background Great progress has been made in understanding the epigenetic regulation of the immune response. However, the influence of RNA N6-methyladenosine (m6A) regulation on the tumor microenvironment (TME) of melanoma is still unknown. Methods We comprehensively evaluated 790 samples of melanoma based on 21 m6A regulator genes and associated these regulators with infiltration characteristics in the TME. We used the m6A score to assess the m6A modification pattern and response to immunotherapy. Results Three distinct m6A modification patterns were identified among 790 melanoma samples, and the patterns correspond to different clinical outcomes. The characteristics of the three modification patterns mainly included three phenotypes: immune inflamed, immune desert and immune excluded. We found that the m6A modification pattern could be applied to assess genetic variations, immune infiltration and prognosis. Based on the m6A score, melanoma patients could be classified into high and low m6A score subgroups. Stromal activation was observed in the high m6A score subgroup, indicating the immune-excluded phenotype. Patients in the low m6A score subgroup had prolonged overall survival and enhanced immune infiltration. Further analysis showed that the low m6A score correlated with a high tumor mutation burden, and better response to anti-PD-1/PD-L1 therapy, which indicated that the low m6A score subgroup might have therapeutic advantages and better clinical effects. Conclusion Our research revealed that m6A modification plays an essential role in shaping TME complexity and diversity of melanoma. Evaluation of m6A modification patterns could provide more information on TME infiltration characteristics and new ideas for immunotherapies.