Cross-talk of different dimensional methylation modification patterns alters tumor microenvironment infiltration and immunotherapy response in renal cancer

Abstract Background Different dimensional methylation modifications, including DNA, RNA and histone methylation, are mediated by different functional regulators and play an indispensable role in tumor progression. However, the cross-talk and underlying mechanisms of these modification patterns in tumorigenesis, tumor microenvironment (TME) disorder and aberrant immune response are still unknown. Methods We summarized the 9 most common types of modifications from different dimensions and revealed transcriptional and genetic alterations of 104 modification regulators in clean cell renal cell carcinoma (ccRCC) patients. Next, we constructed a prognosis-correlation network to further explore their interactions and identified distinct methylation modification patterns by using unsupervised clustering algorithm. Lastly, we constructed a methylation modification regulator score (MMR Score) model to quantify the characterizations of different modification patterns for individual patients, and validated its predictive value to immunotherapy response. Results We investigated the interactions between different dimensional modifications and identified critical negative regulated nodes in the prognosis-correlation network. Our clustering results revealed that, different from other cancers, immune activity in ccRCC not only depended on the abundance of immune cells, but also the infiltration of stromal cells. The MMR Score for the quantification of each patient can act as an effective biomarker to predict clinical outcomes. Patients with high MMR Score were more likely to experience a therapeutic advantage and clinical benefits from immunotherapy. Conclusions This work revealed that cross-talk of different modifications could lead to the complexity and heterogeneity of individual TME. The integrated quantification of individual modification patterns can better guide clinical personalized cancer treatments.