Pan-sarcoma characterization of lncRNAs in the crosstalk of EMT and tumor immunity identifies distinct clinical outcomes and potential implications for immunotherapy

Abstract The epithelial-to-mesenchymal transition (EMT) is a reversible process that may interact with tumor immunity through multiple approaches. Increasing evidence has demonstrated the interconnections among EMT-related processes, tumor microenvironment, immune activity, as well as the potential influence on immunotherapy response. Long non-coding RNAs (lncRNAs) are emerging as critical modulators of gene expression. They can play fundamental roles in tumor immunity and act as promising biomarkers of immunotherapy response. However, the potential roles of lncRNA in the crosstalk of EMT and tumor immunity are still unclear in sarcoma. We obtained multi-omics profiling of 1440 pan-sarcoma patients from 19 datasets. Through an unsupervised consensus clustering approach, we categorized EMT molecular subtypes. We subsequently identified 26 EMT molecular subtype and tumor immune-related lncRNAs (EILncRNA) across pan-sarcoma types and developed an EILncRNA signature-based weighted scoring model (EILncSig). The EILncSig presented a favorable performance in predicting the prognosis of sarcoma, and the high-EILncSig was associated with exclusive TME characteristics with desert-like infiltration of immune cells. Multiple altered pathways, somatically mutated genes and recurrent CNV regions associated with EILncSig were identified. Notably, the EILncSig was associated with the efficacy of immune checkpoint inhibition (ICI) therapy. We additionally screened compounds such as Irinotecan that may have the potential to convert the EILncSig phenotype. By integrative analysis on multi-omics profiling, our findings provide a comprehensive resource for understanding the functional role of lncRNA-mediated immune regulation in sarcomas, which may advance the understanding of tumor immune response and the development of lncRNA-based immunotherapeutic strategies for sarcoma.