Abstract
BackgroundThe epigenetic regulation of immune response has been demonstrated in recent studies. Nonetheless, potential roles of RNA N6-methyladenosine (m6A) modification in tumor microenvironment (TME) cell infiltration remain unknown.MethodsWe comprehensively evaluated the m6A modification patterns of 1938 gastric cancer samples based on 21 m6A regulators, and systematically correlated these modification patterns with TME cell-infiltrating characteristics. The m6Ascore was constructed to quantify m6A modification patterns of individual tumors using principal component analysis algorithms.ResultsThree distinct m6A 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 m6A 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.ConclusionsThis work revealed the m6A modification played a nonnegligible role in formation of TME diversity and complexity. Evaluating the m6A modification pattern of individual tumor will contribute to enhancing our cognition of TME infiltration characterization and guiding more effective immunotherapy strategies.Graphical abstract
Highlights
In all living organisms, as the third layer of epigenetics, more than 150 RNA modifications including 5methylcytosine (m5C), N6-methyladenosine (m6A) and N1-methyladenosine (m1A) have been identified [1, 2]
We revealed three distinct m6A modification patterns, and surprisingly found that the TME characteristics under these three patterns were highly consistent with the immuneexcluded phenotype, immune-inflamed phenotype and immune-desert phenotype, respectively, suggesting the m6A modification played a nonnegligible role in shaping individual tumor microenvironment characterizations
It was found that the ZC3H13 exhibited the highest mutation frequency followed by KIAA1429, while both demethylases (FTO and ALKBH5) as well as METTL3 did not show any mutations in gastric cancer (GC) samples (Fig. 1b)
Summary
As the third layer of epigenetics, more than 150 RNA modifications including 5methylcytosine (m5C), N6-methyladenosine (m6A) and N1-methyladenosine (m1A) have been identified [1, 2]. The TME cell-infiltrating characteristics under these three patterns were highly consistent with the three immune phenotypes of tumors including immuneexcluded, immune-inflamed and immune-desert phenotypes. We demonstrated the evaluation of m6A 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 immuneexclusion TME phenotype, with poorer survival. Two immunotherapy cohorts confirmed patients with lower m6Ascore demonstrated significant therapeutic advantages and clinical benefits
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