Abstract
BACKGROUND: Immune-related genes (IRGs) have been confirmed to have an important role in tumorigenesis and tumor microenvironment formation. Nevertheless, a systematic analysis of IRGs and their clinical significance in soft tissue sarcoma (STS) patients is lacking. METHODS: Gene expression files from The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) were used to select differentially expressed genes (DEGs). Differentially expressed immune-related genes (DEIRGs) were determined by matching the DEG and ImmPort gene sets, which were evaluated by functional enrichment analysis. Unsupervised clustering of the identified DEIRGs was conducted, and associations with prognosis, the tumor microenvironment (TME), immune checkpoints, and immune cells were analyzed simultaneously. Two prognostic signatures, one for overall survival (OS) and one for progression free survival (PFS), were established and validated in an independent set. Finally, two transcription factor (TF)-IRG regulatory networks were constructed, and a crucial regulatory axis was validated. RESULTS: In total, 364 DEIRGs and four clusters were identified. OS, TME scores, five immune checkpoints, and 12 types of immune cells were found to be significantly different among the four clusters. The two prognostic signatures incorporating 20 DEIRGs showed favorable discrimination and were successfully validated. Two nomograms combining signature and clinical variables were generated. The C-indexes were 0.879 (95%CI 0.832 ~ 0.926) and 0.825 (95%CI 0.776 ~ 0.874) for the OS and PFS signatures, respectively. Finally, TF-IRG regulatory networks were established, and the MYH11-ADM regulatory axis was verified in three independent datasets. CONCLUSION: This comprehensive analysis of the IRG landscape in soft tissue sarcoma revealed novel IRGs related to carcinogenesis and the immune microenvironment. These findings have implications for prognosis and therapeutic responses, which reveal novel potential prognostic biomarkers, promote precision medicine, and provide potential novel targets for immunotherapy.