m(6)A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer

BACKGROUND: The epigenetic regulation of immune response has been demonstrated in recent studies. Nonetheless, potential roles of RNA N6-methyladenosine (m(6)A) modification in tumor microenvironment (TME) cell infiltration remain unknown. METHODS: We comprehensively evaluated the m(6)A modification patterns of 1938 gastric cancer samples based on 21 m(6)A regulators, and systematically correlated these modification patterns with TME cell-infiltrating characteristics. The m6Ascore was constructed to quantify m(6)A modification patterns of individual tumors using principal component analysis algorithms. RESULTS: Three distinct m(6)A modification patterns were determined. The TME cell-infiltrating characteristics under these three patterns were highly consistent with the three immune phenotypes of tumors including immune-excluded, immune-inflamed and immune-desert phenotypes. We demonstrated the evaluation of m(6)A modification patterns within individual tumors could predict stages of tumor inflammation, subtypes, TME stromal activity, genetic variation, and patient prognosis. Low m6Ascore, characterized by increased mutation burden and activation of immunity, indicated an inflamed TME phenotype, with 69.4% 5-year survival. Activation of stroma and lack of effective immune infiltration were observed in the high m6Ascore subtype, indicating a non-inflamed and immune-exclusion TME phenotype, with poorer survival. Low m6Ascore was also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. Two immunotherapy cohorts confirmed patients with lower m6Ascore demonstrated significant therapeutic advantages and clinical benefits. CONCLUSIONS: This work revealed the m(6)A modification played a nonnegligible role in formation of TME diversity and complexity. Evaluating the m(6)A modification pattern of individual tumor will contribute to enhancing our cognition of TME infiltration characterization and guiding more effective immunotherapy strategies. GRAPHICAL ABSTRACT: [Image: see text]