Landscape Of M6a RNA Methylation Regulators and Tumor Microenvironment Cell-Infiltration Characterization In Gastroesophageal Adenocarcinomas

Abstract

Background: RNA N6-methyladenosine (m6A) modification plays a nonnegligible role in shaping individual tumor microenvironment (TME) characterizations. However, the landscape and relationship of m6A modification and TME cell infiltration remain unknown in gastroesophageal adenocarcinomas (GEA). Methods: We systematically examined the TME of GEA focusing on the distinct m6A modification patterns from the public databases. Intrinsic patterns of m6A modification were evaluated for associations with clinicopathological characteristics, underlying biological pathways, tumor immune cell infiltration, oncological outcomes and treatment responses. We generated a single-cell transcriptome atlas of the GEA sample inhouse to validate the role of the m6A modification pattern on TME.Results: We identified and validated the landscape of m6A regulators and tumor-infiltrating immune cells in GEA. Then, two distinct m6A modification patterns of GEA (cluster1/2 subgroup) were defined, and we correlated two subgroups with TME cell-infiltrating characteristics. Cluster2 subgroup correlates with a poorer prognosis, down-regulated PD-1 expression, higher risk scores and distinct immune cell infiltration. Additionally, PPI and WGCNA network analysis were integrated to identify key module genes closely related to immune infiltration of GEA to find immunotherapy markers. And COL4A1 and COL5A2 in brown module were significantly correlated to the prognosis, PD-1/L1 and CTLA-4 expression of GEA patients. Interesting, low COL5A2 expression was linked to an enhanced response to anti-PD-1 immunotherapy. Finally, a prognostic risk score was constructed using three m6A regulator-associated signatures that represented an independent prognosis factor for GEA. The single-cell transcriptome atlas of GEA sample validated the role of m6A modification pattern on TME and revealed that three m6A regulators are highly expressed in CD4+ T cells, CD8+ T cells, Tregs and Macrophages.Conclusions: Our work revealed m6A RNA methylation regulators are a type of vital participant in the malignant progression and TME diversity of GEA. m6A modification patterns of COL5A2 may be the potential biomarker contributes to predicting the response to anti-PD-1 immunotherapy.