Crosstalk Of Methylation Modification Regulators Alters Tumor Microenvironment And Immunotherapy Response In Renal Cancer

Objective:In recent years,the important role of methylation modification in the occurrence and development of tumor and drug resistance has been discovered.Different dimensional methylation modifications,including DNA,RNA and histone methylations,are mediated by different functional regulators.However,the crosstalk and underlying mechanism of these modification patterns in tumorigenesis,metastasis,recurrence and therapy resistance are still unknown.Therefore,exploring the cross-talk patterns of methylated regulators of different dimensions will improve the understanding of tumor immune regulation and immunotherapy,and is of great significance to guide the individualized treatment of patients with ccRCC.Method:In this study,we selected the most common methylation modification types in DNA,RNA and histone,and explored the genetic and transcriptional changes of their regulators in patients with ccRCC.And the crosstalk patterns of methylation modification regulators in different dimensions were investigated.By univariate Cox regression analysis,prognostic regulators were screened.Unsupervised cluster analysis was performed based on expression data of prognostic related regulators,and survival analysis was performed for different subtypes.Further,the tumor stemness and genomic variation of different subtypes were analyzed,and the characteristics of tumor immune microenvironment in different subtypes were discussed.The gene expression difference of the subtypes with the best prognosis and the worst prognosis was analyzed,and the GO and KEGG pathway enrichment analysis was performed for the differentially expressed genes.Through the workflow of "univariate CoxLASSO regression-multivariate Cox",core genes were screened out to construct the methylation-modification crosstalk score model.The relationship between the score model and prognosis of patients was analyzed,and the application of the score model in immunotherapy and targeted drug selection was discussed.Results:In this study,we systematically analyzed 3 most common types of methylation modification in DNA,RNA and histone dimensions,revealing the genetic and transcriptional changes of 52 modification regulators in patients with ccRCC.We found that the crosstalk of different dimensional methylation modification was prevalent,and genes regulated by multiple methylation modifications were identified.Subsequently,three distinct subtypes were identified based on the expression of 30 prognostic regulators.Subtype B presented the lowest expression of regulators and worst prognosis while Subtype C presented the highest expression of regulators and best prognosis.Characteristics of the subtype B were high abundance of antigen exposure and immune infiltration,but the high level of stemness,and significant dysfunction of CD8+T cell might be the reason for poor survival outcomes.4738 differentially expressed genes were screened between subtype B and subtype C.Using GO and KEGG pathway enrichment analyses,we found that these differentially expressed genes related to PD-L1 expression and PD-1 checkpoint pathway,regulation of T cell and B cell receptor,differentiation of helper T cells and expression of chemokine.we constructed a crosstalk-related signature including 9 core genes and obtained a score(MMC score)for each ccRCC patient.The patients with low MMC score were more inclined to experience malignant progression and worse overall survival.After immunotherapy,patients with low MMC scores significantly improved overall survival and had a higher objective response rate than patients with high scores.At the same time,the same results were also observed in other urologic cancer.Our results suggested patients with low MMC score might be suitable for immunotherapy and RITA,pazopanib might be a good choice for patients with high MMC score.Conclusion:In this study,we comprehensively and systematically analyzed the cross-talk patterns between different dimensions of methylation modification,revealing its impact on the tumor microenvironment and prognosis of patients with ccRCC.We constructed a score model to quantify the characteristics of different methylation modification patterns for each individual patient.MMC score can serve as a valuable biomarker to guide clinical selection of immunotherapy and targeted drugs and help to improve personalized ccRCC treatment.