Predictive role of ferroptosis-related long non-coding RNAs in bladder cancer and their association with immune microenvironment and immunotherapy response.

BACKGROUND: We have previously reported that ferroptosis has an important role in bladder cancer development. In this study, we aimed to further explore the possible predictive ability of ferroptosis-related long non-coding RNAs (lncRNAs) in bladder cancer and their relation with immune microenvironment and immunotherapy response. MATERIALS AND METHODS: The ferroptosis-related lncRNAs were identified by Pearson's correlation analysis. The predictive lncRNA signature was developed by univariate and multivariate regression analyses. Only the main effects of independent variables in multivariate analysis were included in this signature. The TCGA dataset was defined as the training cohort and GEO was the validation cohort in this study. All samples were grouped into a high- or low-risk group depending on risk signature. The prognostic role of lncRNA signature was explored through survival analysis and receiver operating characteristic curve (ROC) analysis in both TCGA and GEO cohorts. Additionally, the independent prognostic ability of the lncRNA signature was confirmed by multivariate independent analysis. Furthermore, the relationship between lncRNAs and immune microenvironment as well as immunotherapy response in bladder cancers was studied. RESULTS: The Kaplan-Meier curves identified significantly poorer overall survival outcomes for high-risk groups in both TCGA (p < 0.001) and GEO (p < 0.001) cohorts. The area under the curve (AUC) during ROC analysis of 1, 3, and 5 years was 0.781 ± 0.046, 0.784 ± 0.027, and 0.817 ± 0.025, respectively, in the TCGA cohort and 0.665 ± 0.177, 0.719 ± 0.068, and 0.791 ± 0.055, respectively, in the GEO cohort. The multivariate independent analysis in TCGA cohort identified age (p = 0.003), stage (p < 0.001), and signature risk score (p < 0.001) as independent risk factors for overall survival. Furthermore, this study demonstrated a significant difference in infiltration levels of various immune cells between high- and low-risk groups. The high risk group tended to have a lower expression of proteins including PD1 (p < 0.01), PD-L1 (p < 0.01), CTLA-4 (p < 0.05), etc. corresponding to various immune checkpoints. Additionally, the immunotherapy trial confirmed that the high-risk group tended to have a poorer treatment response than the low-risk group (p < 0.001). CONCLUSIONS: The ferroptosis-related lncRNAs exhibited a good predictive capacity for overall survival in bladder cancer. Additionally, they could be utilized to reveal tumour-immune microenvironment and immunotherapy responses.