[HTML][HTML] m6A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer

W Chong, L Shang, J Liu, Z Fang, F Du, H Wu, Y Liu… - Theranostics, 2021 - ncbi.nlm.nih.gov
W Chong, L Shang, J Liu, Z Fang, F Du, H Wu, Y Liu, Z Wang, Y Chen, S Jia, L Chen, L Li…
Theranostics, 2021ncbi.nlm.nih.gov
Recent studies have highlighted the biological significance of RNA N 6-methyladenosine (m
6 A) modification in tumorigenicity and progression. However, it remains unclear whether m
6 A modifications also have potential roles in immune regulation and tumor
microenvironment (TME) formation. Methods: In this study, we curated 23 m 6 A regulators
and performed consensus molecular subtyping with NMF algorithm to determine m 6 A
modification patterns and the m 6 A-related gene signature in colon cancer (CC). The …
Abstract
Recent studies have highlighted the biological significance of RNA N 6-methyladenosine (m 6 A) modification in tumorigenicity and progression. However, it remains unclear whether m 6 A modifications also have potential roles in immune regulation and tumor microenvironment (TME) formation.
Methods: In this study, we curated 23 m 6 A regulators and performed consensus molecular subtyping with NMF algorithm to determine m 6 A modification patterns and the m 6 A-related gene signature in colon cancer (CC). The ssGSEA and CIBERSORT algorithms were employed to quantify the relative infiltration levels of various immune cell subsets. An PCA algorithm based m 6 Sig scoring scheme was used to evaluate the m 6 A modification patterns of individual tumors with an immune response.
Results: Three distinct m6A modification patterns were identified among 1307 CC samples, which were also associated with different clinical outcomes and biological pathways. The TME characterization revealed that the identified m 6 A patterns were highly consistent with three known immune profiles: immune-inflamed, immune-excluded, and immune-desert, respectively. Based on the m 6 Sig score, which was extracted from the m 6 A-related signature genes, CC patients can be divided into high and low score subgroups. Patients with lower m 6 Sig score was characterized by prolonged survival time and enhanced immune infiltration. Further analysis indicated that lower m 6 Sig score also correlated with greater tumor mutation loads, PD-L1 expression, and higher mutation rates in SMGs (eg, PIK3CA and SMAD4). In addition, patients with lower m 6 Sig scores showed a better immune responses and durable clinical benefits in three independent immunotherapy cohorts.
Conclusions: This study highlights that m 6 A modification is significantly associated with TME diversity and complexity. Quantitatively evaluating the m 6 A modification patterns of individual tumors will strengthen our understanding of TME characteristics and promote more effective immunotherapy strategies.
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