Bladder cancer ranks as the 10th most common cancer worldwide, with deteriorating prognosis as the disease advances. While immune checkpoint inhibitors (ICIs) have shown promise in clinical therapy in both operable and advanced bladder cancer, identifying patients who will respond is challenging. Anoikis, a specialized form of cell death that occurs when cells detach from the extracellular matrix, is closely linked to tumor progression. Here, we aimed to explore the anoikis-based biomarkers for bladder cancer prognosis and immunotherapeutic decisions. Through consensus clustering, we categorized patients from the TCGA-BLCA cohort into two clusters based on anoikis-related genes (ARGs). Significant differences in survival outcome, clinical features, tumor immune environment (TIME), and potential ICIs response were observed between clusters. We then formulated a four-gene signature, termed "Ascore", to encapsulate this gene expression pattern. The Ascore was found to be closely associated with survival outcome and served as an independent prognosticator in both the TCGA-BLCA cohort and the IMvigor210 cohort. It also demonstrated superior predictive capacity (AUC = 0.717) for bladder cancer immunotherapy response compared to biomarkers like TMB and PD-L1. Finally, we evaluated Ascore’s independent prognostic performance as a non-invasive biomarker in our clinical cohort (Gulou-Cohort1) using circulating tumor cells detection, achieving an AUC of 0.803. Another clinical cohort (Gulou-Cohort2) consisted of 40 patients undergoing neoadjuvant anti-PD-1 treatment was also examined. Immunohistochemistry of Ascore in these patients revealed its correlation with the pathological response to bladder cancer immunotherapy (P = 0.004). Impressively, Ascore (AUC = 0.913) surpassed PD-L1 (AUC = 0.662) in forecasting immunotherapy response and indicated better net benefit. In conclusion, our study introduces Ascore as a novel, robust prognostic biomarker for bladder cancer, offering a new tool for enhancing immunotherapy decisions and contributing to the tailored treatment approaches in this field.

中文翻译：

---

Ascore 的多队列验证：基于失巢凋亡的预后特征，用于预测膀胱癌的疾病进展和免疫治疗反应

膀胱癌是全球第十大常见癌症，随着疾病的进展，预后不断恶化。虽然免疫检查点抑制剂 (ICIs) 在可手术和晚期膀胱癌的临床治疗中显示出前景，但确定有反应的患者仍具有挑战性。失巢凋亡是细胞从细胞外基质脱离时发生的一种特殊形式的细胞死亡，与肿瘤进展密切相关。在这里，我们的目的是探索基于失巢凋亡的生物标志物用于膀胱癌预后和免疫治疗决策。通过共识聚类，我们根据失巢凋亡相关基因 (ARG) 将 TCGA-BLCA 队列中的患者分为两类。在不同簇之间观察到生存结果、临床特征、肿瘤免疫环境 (TIME) 和潜在 ICI 反应的显着差异。然后，我们制定了一个称为“Ascore”的四基因特征来封装该基因表达模式。研究发现 Ascore 与生存结果密切相关，并且在 TCGA-BLCA 队列和 IMvigor210 队列中均可作为独立的预后指标。与 TMB 和 PD-L1 等生物标志物相比，它还表现出对膀胱癌免疫治疗反应的卓越预测能力 (AUC = 0.717)。最后，我们使用循环肿瘤细胞检测评估了 Ascore 作为非侵入性生物标志物在我们的临床队列 (Gulou-Cohort1) 中的独立预后性能，AUC 为 0.803。另一个临床队列（Gulou-Cohort2）由 40 名接受新辅助抗 PD-1 治疗的患者组成。这些患者的 Ascore 免疫组织化学显示其与膀胱癌免疫治疗的病理反应相关（P = 0.004）。令人印象深刻的是，Ascore (AUC = 0.913) 在预测免疫治疗反应方面超过了 PD-L1 (AUC = 0.662)，并显示出更好的净效益。总之，我们的研究将 Ascore 作为一种新型、稳健的膀胱癌预后生物标志物，为增强免疫治疗决策并为该领域的定制治疗方法做出贡献提供了一种新工具。