M5C modulator mediated methylation pattern and TME cell infiltration in bladder cancer

Background: In recent studies, the role of modification patterns of N6-methyladenosine (m6A) regulators in tumor microenvironment (TME) cell infiltration in the tumor microenvironment has been identified. However, the role of 5-methylcytosine (m5C) modification patterns in TME cell infiltration remains to be discovered. Methods: In this study, 660 bladder cancer patients were enrolled to comprehensively evaluate the m5C modification pattern based on 13 m5C regulators, and to explore the association between m5C modification pattern and TME cell infiltration status. Finally, PRINCIPAL component analysis (PCA) algorithm constructed m5Cscore, which was used to evaluate and quantify individual m5C modification patterns. Results: Our study identified three distinct m5C modification patterns in bladder cancer. Studies showed that TME cell infiltration characteristics under these three modification patterns were highly associated with three tumor immunophenotypes (immune-inflamed, immune-excluded, immune-desert). In addition, m5C methylation modification patterns were proved to be able to predict tumor disease progression, genetic variation and prognosis of patients. The individualized scoring system – m5Cscore, which was based on m5C methylation modification, showed great differences in tumor mutation burden (TMB), clinical characteristics, immune checkpoint and immunotherapy. The low m5Cscore group was characterized by matrix activation and lack of effective immune cell infiltration, indicating the immune-excluded phenotype. The higher m5Cscore group showed fewer PD-L1 mutations, which were associated with a promoted response to PD-L1/PD-1 immunotherapy and a better prognosis. Conclusions: This work confirmed the extensive regulatory mechanisms of the m5C modification pattern in the tumor microenvironment. The m5C modification pattern functioned as an important element of forming the heterogeneity and complexity of TME landscape. Understanding and in-depth evaluation of individual m5C modification patterns would help us understand the TME landscape and guide better immunotherapy strategies.