免疫检查点阻滞（ICB）和抗血管生成药物的联合应用已经延长了晚期肾细胞癌（RCC）患者的生存时间。但是，并不是所有的患者都能从这种干预中获得临床益处。在这项研究中，我们的目标是建立一个有前途的免疫相关预后模型，以分层响应ICB和抗血管生成药物的联合应用的患者，并促进个体化治疗的开发。基于IMmotion151队列中407名晚期RCC患者的临床注释和RNA测序（RNA-seq）数据，通过加权基因共表达网络分析，鉴定出响应atezolizumab（抗程序性死亡配体1抗体）加bevacizumab（抗血管内皮生长因子抗体）治疗的受试者和非受试者之间的九个免疫关联差异表达基因（DEGs）。 我们还进行了单样本基因集富集分析，开发了一种新的免疫相关风险评分（IRS）模型，并通过预测肾癌患者对化疗的敏感性和对免疫治疗的反应性进一步估计其预后。利用JAVELIN Renal 101队列，E-MTAB-3218队列，IMvigor210队列和GSE78220队列对IRS模型进行进一步验证。利用接收器操作特征曲线评估了IRS模型对晚期RCC的预测意义。 IRS模型是由九个免疫关联DEGs构建的，分别是SPINK5，SEMA3E，ROBO2，BMP5，ORM1，CRP，CTSE，PMCH和CCL3L1。高IRS的晚期RCC患者存在不良临床结局的高风险（危险比=1.91；95％置信区间=1.43-2.55；P <0.0001）。转录组分析表明，IRS低组表现出显著高的CD8+ T效应细胞、抗原处理机制和免疫检查点表达水平，而IRS高组富集上皮间质转化通路。IRS模型能有效区分响应ICB联合抗血管生成阻滞治疗或单独免疫治疗的受试者和非受试者，在IMmotion151队列中的曲线下面积值为0.822，在JAVELIN Renal 101队列中为0.751，在E-MTAB-3218队列中为0.776。 IRS模型是一种可靠和强健的免疫标签，可用于患者选择，以优化ICB加抗血管生成药物治疗对晚期RCC的疗效。版权所有©2023 Chen，Bi，Tan，Jian和Yu。

Immune checkpoint blockade (ICB) and anti-angiogenic drug combination has prolonged the survival of patients with advanced renal cell carcinoma (RCC). However, not all patients receive clinical benefits from this intervention. In this study, we aimed to establish a promising immune-related prognostic model to stratify the patients responding to ICB and anti-angiogenic drug combination and facilitate the development of personalized therapies for patients with RCC.Based on clinical annotations and RNA-sequencing (RNA-seq) data of 407 patients with advanced RCC from the IMmotion151 cohort, nine immune-associated differentially expressed genes (DEGs) between responders and non-responders to atezolizumab (anti-programmed death-ligand 1 antibody) plus bevacizumab (anti-vascular endothelial growth factor antibody) treatment were identified via weighted gene co-expression network analysis. We also conducted single-sample gene set enrichment analysis to develop a novel immune-related risk score (IRS) model and further estimate the prognosis of patients with RCC by predicting their sensitivity to chemotherapy and responsiveness to immunotherapy. IRS model was further validated using the JAVELIN Renal 101 cohort, the E-MTAB-3218 cohort, the IMvigor210 and GSE78220 cohort. Predictive significance of the IRS model for advanced RCC was assessed using receiver operating characteristic curves.The IRS model was constructed using nine immune-associated DEGs: SPINK5, SEMA3E, ROBO2, BMP5, ORM1, CRP, CTSE, PMCH and CCL3L1. Advanced RCC patients with high IRS had a high risk of undesirable clinical outcomes (hazard ratio = 1.91; 95% confidence interval = 1.43-2.55; P < 0.0001). Transcriptome analysis revealed that the IRS-low group exhibited significantly high expression levels of CD8+ T effectors, antigen-processing machinery, and immune checkpoints, whereas the epithelial-mesenchymal transition pathway was enriched in the IRS-high group. IRS model effectively differentiated the responders from non-responders to ICB combined with angiogenesis blockade therapy or immunotherapy alone, with area under the curve values of 0.822 in the IMmotion151 cohort, 0.751 in the JAVELIN Renal 101 cohort, and 0.776 in the E-MTAB-3218 cohort.IRS model is a reliable and robust immune signature that can be used for patient selection to optimize the efficacy of ICB plus anti-angiogenic drug therapies in patients with advanced RCC.Copyright © 2023 Chen, Bi, Tan, Jian and Yu.