新型铜死亡模式与膀胱癌肿瘤免疫微环境特征。

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 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.

背景：膀胱癌（UCB）是全球最常见的泌尿系统恶性肿瘤，尽管有多种治疗选择，但复发率仍然很高。铜死亡是一种独特的新型铜依赖性程序性细胞死亡机制，其对肿瘤免疫微环境、临床病理特征和患者预后的综合影响在很大程度上仍不清楚。

方法：我们根据先前报道的 10 个铜死亡相关基因，从 TCGA 和 GEO 下载的数据中对 568 例 UCB 样本进行了全面的铜死亡模式检查。然后，对各种模式下不同的基因进行单因素 COX 回归分析。为了衡量个体铜死亡模式，我们使用主成分分析算法构建了一个铜死亡评分系统。为了验证评分系统，我们对不同病理分级的肿瘤组织进行了免疫组织化学染色，并对与预后相关的差异表达基因进行了实验。最后，我们使用 IMvigor 210 队列的数据验证了评分系统预测免疫治疗反应的能力。

结果：通过研究，我们最终发现了四个独特的铜死亡簇和两个基因簇。不同铜死亡簇和基因簇的患者临床特征和预后以及肿瘤组织的 mRNA 转录组、通路富集和 TME 中的免疫细胞浸润差异巨大。为了确定 UCB 患者的个体铜死亡模式，我们还建立了一个铜死亡评分系统。通过多种方法验证后，结果表明该评分系统可以预测 UCB 患者的预后，与 TNM 分期、肿瘤分级、分子类型和最终生存状态等临床特征显著相关。根据肿瘤突变负担结合评分系统可以有效地预测 UCB 患者的临床结局。此外，我们发现铜死亡评分与免疫治疗反应和化疗敏感性有显著相关性。

结论：本研究揭示了铜死亡对 UCB 肿瘤免疫微环境和临床病理特征的潜在影响。铜死亡评分系统可以有效地预测患者的预后以及对化疗和免疫治疗的反应。