Comprehensive Evaluation of the m(6)A Regulator Prognostic Risk Score in the Prediction of Immunotherapy Response in Clear Cell Renal Cell Carcinoma

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is known for its high drug resistance. The tumor-immune crosstalk mediated by the epigenetic regulation of N6-methyladenosine (m(6)A) modification has been demonstrated in recent studies. Therefore, m(6)A modification-mediated immune cell infiltration characteristics may be helpful to guide immunotherapy for ccRCC. METHODS: This study comprehensively analyzed m(6)A modifications using the clinical parameters, single-cell RNA sequencing data, and bulk RNA sequencing data from the TCGA-ccRC cohort and 13 external validation cohorts. A series of bioinformatic approaches were applied to construct an m(6)A regulator prognostic risk score (MRPRS) to predict survival and immunotherapy response in ccRCC patients. Immunological characteristics, enriched pathways, and mutation were evaluated in high- and low-MRPRS groups. RESULTS: The expressional alteration landscape of m(6)A regulators was profiled in ccRCC cell clusters and tissue. The 8 regulator genes with minimal lambda were integrated to build an MRPRS, and it was positively correlated with immunotherapeutic response in extent validation cohorts. The clinicopathological features and immune infiltration characteristics could be distinguished by the high- and low-MRPRS. Moreover, the MRPRS-mediated mutation pattern has an enhanced response to immune checkpoint blockade in the ccRCC and pan-cancer cohorts. CONCLUSIONS: The proposed MRPRS is a promising biomarker to predict clinical outcomes and therapeutic responses in ccRCC patients.