A novel cuproptosis pattern and tumor immune microenvironment characterization in urothelial carcinoma of the bladder

BACKGROUND: Urothelial carcinoma of the bladder (UCB) is the most prevalent malignant tumor of the urinary system worldwide, which has a significant recurrence rate despite multiple treatment options available. As a unique and novel copper-dependent programmed cell death mechanism, the comprehensive impact of cuproptosis on the tumor immune microenvironment, clinicopathological characteristics and the prognosis of patients remains largely unclear. METHODS: A total of 568 UCB samples were thoroughly examined for cuproptosis patterns using data downloaded from TCGA and GEO, based on 10 cuproptosis-related genes reported previously. Then, the univariate COX regression analysis was performed on the genes that differed across the various patterns. To measure individual cuproptosis pattern, a cuproptosis score system was constructed using a principal component analysis algorithm. To validate the scoring system, immunohistochemical staining was performed on tumor tissues with different pathological grades, and experiments in vitro were conducted about the differentially expressed genes related to prognosis. Finally, the capacity of scoring system to predict the response to immunotherapy was verified by using data from IMvigor 210 cohort. RESULTS: Four unique cuproptosis clusters and two gene clusters were finally found by the investigation. The clinical features and prognosis of patients, as well as the mRNA transcriptome, pathway enrichment, and immune cell infiltration in TME, varied dramatically between various cuproptosis clusters and gene clusters. To identify individual cuproptosis patterns in UCB patients, we also established a cuproptosis scoring system. After validation with multiple methods, it was indicated that the score system could predict the prognosis of UCB patients and was significantly connected to clinical features such TNM category, tumor grade, molecular type and ultimate survival status. The clinical outcomes of UCB patients were predicted effectively according to the tumor mutation burden in conjunction with the scoring system. Furthermore, we found that the cuproptosis score had a significant correlation with the response to immunotherapy and the sensitivity to chemotherapy. CONCLUSION: This study revealed the potential impact of cuproptosis on the UCB tumor immune microenvironment and clinical pathological characteristics. The cuproptosis score system could effectively predict the prognosis of patients and the response to chemotherapy and immunotherapy.