Clinical Prognosis and Immunotherapy Value of m 6 A RNA Methylation Regulators and Tumor Microenvironment Cell-Infiltration Characterization in Gastroesophageal Adenocarcinomas

Background: RNA N6-methyladenosine (m6A) modification plays a nonnegligible role in shaping individual tumor microenvironment (TME) characterizations. However, the potential roles of m6A modification in 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. Single-cell transcriptome atlas of the GEA samples inhouse was applied to validate our findings. Findings: We identified two distinct m6A modification patterns of GEA (cluster1/2 subgroup), and 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. 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. Single-cell transcriptome atlas revealed that three m6A regulators are highly expressed in CD4+ T cells, CD8+ T cells, Tregs and Macrophages. Interpretations: Our work suggested m6A RNA methylation regulators are a type of vital participant in the malignant progression and TME diversity of GEA, which help to interpret the responses of GEA to immunotherapies and provide new sight for cancer treatment. Funding Statement: This study was financially supported by the National Natural Science Foundation of China (Nos. 31671468 and 31970728), the Academic Promotion Programm of Shandong First Medical University (No. 2019QL024), the Shandong Provincial Natural Science Foundation of China (Nos. ZR2016HM15, ZR2020LZL005, ZR2020MH050). Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: The relevant data TCGA and GEO provided is publicly available and open source; hence, approval by a local ethics committee was not required.