The effect of m6A RNA methylation regulators on tumor microenvironment in clear cell renal cell carcinoma

Abstract

Background: m6A RNA methylation and tumor microenvironment (TME) have been reported to play important roles in the progression and prognosis of clear cell renal cell carcinoma (ccRCC). However, whether m6A RNA methylation regulators affect TME in ccRCC remains unknown. Thus, the current study is designed to comprehensively evaluate the effect of m6A RNA methylation regulators on TME in ccRCC.Methods: Transcriptome data of ccRCC was obtained from The Cancer Genome Atlas (TCGA) database. Consensus clustering analysis was conducted based on the expressions of m6A RNA methylation regulators. Survival differences were evaluated by Kaplan-Meier (K-M) analysis between the clusters. DESeq2 package was used to analyze the differentially expressed genes (DEGs) between the clusters. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were analyzed by ClusterProfiler R package. Immune, stromal and ESTIMATE scores were assessed by ESTIMATE algorithm. CIBERSORT algorithm was applied to evaluate immune infiltration. The expressions of human leukocyte antigen (HLA), immune checkpoint molecules, and Th1/IFNγ gene signature associated with TME were also compared between the clusters. TIDE algorithm and subclass mapping were used to analyze the clinical response of different clusters to PD-1 and CTLA-4 blockade. Results: The expressions of fifteen m6A regulators were significantly different between ccRCC and normal kidney tissues. Based on the expressions of those fifteen m6A regulators, two clusters were identified by consensus clustering, in which cluster 1 had better overall survival (OS). A total of 4,429 DEGs were found between the two clusters, and were enriched into immune-related biological processes. Further analysis of the two clusters’ TME showed that cluster 1 had lower immune and ESTIMATE scores, higher expressions of HLA and lower expressions of immune checkpoint molecules. Besides, immune infiltration and the expressions of Th1/IFNγ gene signature also have significant differences between two clusters. Conclusions: Our study revealed that m6A regulators were important participants in the development of ccRCC, with a close relationship with TME.