Gong Zheng, He Yuming, Mi Xiao, Li Chengcheng, Sun Xiaoran, Wang Guoqiang, Li Leo, Han Yusheng, Xu Chunwei, Wang Wenxian, Cai Shangli, Wang Liang, Liu Zhongyuan
Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110001, China.
Burning Rock Biotech, Guangzhou 510300, China.
Aging (Albany NY). 2023 Sep 24;15(18):9479-9498. doi: 10.18632/aging.205022.
Immune checkpoint inhibitors (ICIs) have shown efficacy in patients with metastatic urothelial cancer (mUC), however, only a small subset of patients could benefit from ICIs. Identifying predictive biomarkers of ICIs in patients with mUC is clinical meaningful for patient stratification and administration.
Clinical and transcriptomic data of mUC patients treated with ICIs from mUC cohort (IMvigor210 study) was utilized to explore the predictive biomarkers. LASSO Cox regression was performed to construct a predictive model. The predictive model was trained and tested in the mUC cohort, and then exploratively tested in clear cell renal cell carcinoma (ccRCC) and melanoma cohorts in which patients also received ICIs regimens.
The differentially expressed genes (DEGs) in complement and coagulation cascades pathway (CCCP) were mainly enriched in non-responders of ICIs in the mUC cohort. A CCCP risk score was constructed based on the DEGs in CCCP. Patients with a low-risk score were more responsive to ICIs and had better overall survival (OS) than those with a high-risk score in the training set (HR, 0.38; 95%CI, 0.27-0.53, P<0.001) and the test set (HR, 0.34; 95%CI, 0.17-0.71, P=0.003). The association between the CCCP risk score and OS remained significant in the multivariable cox regression by adjusting PD-L1 expression and TMB (P<0.05). In addition, there was no difference for OS in the bladder cancer patients without ICIs (TCGA-BLCA cohort, HR, 0.76, 95%CI, 0.49-1.18, P=0.22), suggesting a predictive but not prognostic effect of the risk score. For the exploratory analysis, consistent results were observed that low-risk group showed superior OS in ccRCC cohort (HR, 0.52, 95%CI, 0.37-0.75, P<0.001) and melanoma cohort (HR, 0.27, 95%CI, 0.12-0.62, P=0.001).
Our study showed that the CCCP risk score is an independent biomarker that predicts the efficacy of ICIs in mUC patients. The patients with a low-risk score tend to have a better response to ICIs and a longer life time probably due to the immune-activated TME. Further studies are needed to validate the clinical utility of the seven-gene signature.
免疫检查点抑制剂（ICIs）已在转移性尿路上皮癌（mUC）患者中显示出疗效，然而，只有一小部分患者能从ICIs中获益。识别mUC患者中ICIs的预测生物标志物对于患者分层和给药具有临床意义。
利用mUC队列（IMvigor210研究）中接受ICIs治疗的mUC患者的临床和转录组数据来探索预测生物标志物。进行LASSO Cox回归以构建预测模型。该预测模型在mUC队列中进行训练和测试，然后在也接受ICIs方案治疗的透明细胞肾细胞癌（ccRCC）和黑色素瘤队列中进行探索性测试。
补体和凝血级联途径（CCCP）中的差异表达基因（DEGs）主要在mUC队列中ICIs的无反应者中富集。基于CCCP中的DEGs构建了CCCP风险评分。低风险评分的患者对ICIs反应更强，在训练集（HR，0.38；95%CI，0.27 - 0.53，P<0.001）和测试集（HR，0.34；95%CI，0.17 - 0.71，P = 0.003）中比高风险评分的患者总生存期（OS）更好。通过调整PD - L1表达和肿瘤突变负荷（TMB），CCCP风险评分与OS之间的关联在多变量Cox回归中仍然显著（P<0.05）。此外，未接受ICIs的膀胱癌患者（TCGA - BLCA队列）的OS没有差异（HR，0.76，95%CI，0.49 - 1.18，P = 0.22），表明风险评分具有预测作用而非预后作用。对于探索性分析，观察到一致的结果，即低风险组在ccRCC队列（HR，0.52，95%CI，0.37 - 0.75，P<0.001）和黑色素瘤队列（HR，0.27，95%CI，0.12 - 0.62，P = 0.001）中显示出更好的OS。
我们的数据表明CCCP风险评分是预测mUC患者中ICIs疗效的独立生物标志物。低风险评分的患者对ICIs的反应可能更好，生存期可能更长，这可能归因于免疫激活的肿瘤微环境。需要进一步研究来验证七基因特征的临床实用性。
