Cross-Talk of Multiple Types of RNA Modification Regulators Uncovers the Tumor Microenvironment and Immune Infiltrates in Soft Tissue Sarcoma

BACKGROUND: Soft-tissue sarcoma (STS) represents a rare and diverse cohort of solid tumors, and encompasses over 100 various histologic and molecular subtypes. In recent years, RNA modifications including m(6)A, m(5)C, m(1)A, and m(7)G have been demonstrated to regulate immune response and tumorigenesis. Nevertheless, the cross-talk among these RNA modification regulators and related effects upon the tumor microenvironment (TME), immune infiltrates, and immunotherapy in STS remain poorly understood. METHODS: In this study, we comprehensively investigated transcriptional and genetic alterations of 32 RNA modification regulators in STS patients from The Cancer Genome Atlas (TCGA) cohort and validated them in the Gene Expression Omnibus (GEO) cohort. Single-cell transcriptomes were introduced to identify regulators within specific cell types, with own sequencing data and RT-qPCR conducted for biological validation. Distinct regulator clusters and regulator gene subtypes were identified by using unsupervised consensus clustering analysis. We further built the regulator score model based on the prognostic regulator-related differentially expressed genes (DEGs), which could be used to quantitatively assess the risk for individual STS patients. The clinical and biological characteristics of different regulator score groups were further examined. RESULTS: A total of 455 patients with STS were included in this analysis. The network of 32 RNA modification regulators demonstrated significant correlations within multiple different RNA modification types. Distinct regulator clusters and regulator gene subtypes were characterized by markedly different prognoses and TME landscapes. The low regulator score group in the TCGA-SARC cohort was characterized by poor prognosis. The robustness of the scoring model was further confirmed by the external validation in GSE30929 and GSE17674. The regulator score was negatively correlated with CD4+ T cell, Th2 cell, and Treg cell recruitment and most immunotherapy-predicted pathways, and was also associated with immunotherapy efficacy. CONCLUSIONS: Overall, our study is the first to demonstrate the cross-talk of RNA modification regulators and the potential roles in TME and immune infiltrates in STS. The individualized assessment based on the regulator score model could facilitate and optimize personalized treatment.