Department of Urology, Qilu Hospital of Shandong University, Jinan, China.
Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, China.
Front Immunol. 2023 May 3;14:1126247. doi: 10.3389/fimmu.2023.1126247. eCollection 2023.
Bladder cancer (BC) or carcinoma (BLCA) is predominantly derived from urothelium and includes non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). Bacillus Calmette-Guerin (BCG) has long been applied for NMIBC to effectively reduce disease recurrence or progression, whereas immune checkpoint inhibitors (ICIs) were recently introduced to treat advanced BLCA with good efficacy. For BCG and ICI applications, reliable biomarkers are required to stratify potential responders for better personalized interventions, and ideally, they can replace or reduce invasive examinations such as cystoscopy in monitoring treatment efficacy. Here we developed the cuproptosis-associated 11 gene signature (CuAGS-11) model to accurately predict survival and response to BCG and ICI regimens in BLCA patients. In both discovery and validation cohorts where BLCA patients were divided into high- and low-risk groups based on a median CuAGS-11 score as the cutoff, the high-risk group was associated with significantly shortened overall survival (OS) and progression-free survival (PFS) independently. The survival predictive accuracy was comparable between CuAGS-11 and stage, and their combination-based nomograms showed high consistence between predicted and observed OS/PFS. The analysis of 3 BLCA cohorts treated with BCG unveiled lower response rates and higher frequencies of recurrence or progression coupled with shorter survival in CuAGS-11 high-risk groups. In contrast, almost none of patients underwent progression in low-risk groups. In IMvigor210 cohort of 298 BLCA patients treated with ICI Atezolizumab, complete/partial remissions were 3-fold higher accompanied by significantly longer OS in the CuAGS-11 low- than high-risk groups ( = 7.018E-06). Very similar results were obtained from the validation cohort ( = 8.65E-05). Further analyses of Tumor Immune Dysfunction and Exclusion (TIDE) scores revealed that CuAGS-11 high-risk groups displayed robustly higher T cell exclusion scores in both discovery ( = 1.96E-05) and validation = 0.008) cohorts. Collectively, the CuAGS-11 score model is a useful predictor for OS/PFS and BCG/ICI efficacy in BLCA patients. For BCG-treated patients, reduced invasive examinations are suggested for monitoring the CuAGS-11 low-risk patients. The present findings thus provide a framework to improve BLCA patient stratification for personalized interventions and to reduce invasive monitoring inspections.
膀胱癌（BC）或膀胱癌（BLCA）主要来源于尿路上皮，包括非肌肉浸润性膀胱癌（NMIBC）和肌肉浸润性膀胱癌（MIBC）。卡介苗（BCG）长期以来一直用于 NMIBC，以有效降低疾病复发或进展的风险，而免疫检查点抑制剂（ICI）最近被引入以治疗晚期 BLCA，疗效良好。对于 BCG 和 ICI 的应用，需要可靠的生物标志物来对潜在的反应者进行分层，以实现更好的个性化干预，理想情况下，它们可以替代或减少膀胱镜检查等侵入性检查，以监测治疗效果。在这里，我们开发了铜死亡相关的 11 个基因特征（CuAGS-11）模型，以准确预测 BLCA 患者对 BCG 和 ICI 方案的生存和反应。在 BLCA 患者根据 CuAGS-11 中位数评分作为截断值分为高风险和低风险组的发现和验证队列中，高风险组与明显缩短的总生存期（OS）和无进展生存期（PFS）独立相关。CuAGS-11 和分期之间的生存预测准确性相当，其基于组合的列线图在预测和观察 OS/PFS 之间表现出高度一致性。对接受 BCG 治疗的 3 个 BLCA 队列的分析表明，CuAGS-11 高风险组的反应率较低，复发或进展的频率较高，生存时间较短。相比之下，低风险组几乎没有患者进展。在接受 ICI Atezolizumab 治疗的 298 例 BLCA 患者的 IMvigor210 队列中，完全/部分缓解率提高了 3 倍，CuAGS-11 低风险组的总生存期明显延长（=7.018E-06）。在验证队列中也得到了非常相似的结果（=8.65E-05）。对肿瘤免疫功能障碍和排除（TIDE）评分的进一步分析表明，CuAGS-11 高风险组在发现（=1.96E-05）和验证队列（=0.008）中均显示出明显更高的 T 细胞排除评分。总的来说，CuAGS-11 评分模型是预测 BLCA 患者 OS/PFS 和 BCG/ICI 疗效的有用指标。对于接受 BCG 治疗的患者，建议对 CuAGS-11 低风险患者进行侵入性检查，以监测病情。本研究结果为 BLCA 患者的个体化干预和减少侵入性监测检查提供了一种分层方法。
