Song Bo, Wu Peishan, Wan Chong, Sun Qiangqiang, Kong Guangqi
Department of Urology, Beijing Luhe Hospital, Capital Medical University, No. 82 Xinhua South Road, Tongzhou District, Beijing, 101149, China.
Precision Medicine Center, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, 314001, Zhejiang, China.
Virchows Arch. 2024 Dec;485(6):1133-1150. doi: 10.1007/s00428-024-03952-z. Epub 2024 Oct 25.
Checkpoint inhibitors (CPIs) have been widely applied in the treatment of patients with bladder cancer (BLCA). However, there is still unmet need to dissect response predict biomarkers. To uncover CPI response-related marker genes in cancer cells, we utilized SCISSOR, integrating single-cell RNA and bulk RNA sequencing data. Transcriptomic and clinical data from IMvigor210, UNC-108, and BCAN/HCRN datasets were collected to evaluate and validate the identified biomarkers and signatures. Additionally, we analyzed TCGA-BLCA and local-BLCA RNA-seq data to investigate alternative splicing events (ASEs). Cell viability was assessed in T24 and UMUC3 cells with RBM17 upregulation or downregulation. Through SCISSOR analysis, we discovered that the expression levels of RBM17, TAP1, and PSMB8 were significantly associated with CPI response. Since PSMB8 displayed a highly positive correlation with TAP1, we developed a CPI response score (CRS) signature based on the expression profiles of RBM17 and TAP1. The CRS demonstrated robust predictive capacity in IMvigor210, UNC-108, and BCAN/HCRN datasets and was associated with higher tumor mutational burden (TMB), PD-L1 expression, and unique genomic features. Notably, RBM17 was not linked to the clinical outcomes of BLCA patients but positively correlated with BLCA cell proliferation in vitro. In the meantime, RBM17 was correlated with higher activity in core biological pathways, including antigen processing machinery, CD8 + T effector cells, cell cycle, DNA damage repair, epithelial-mesenchymal transition, histone regulation, and immune checkpoints. Moreover, the high-RBM17 group showed enrichment of LumU/Ba/sq subtypes but fewer FGFR3 alterations. Lastly, RBM17 significantly upregulated ASEs in BLCA samples, leading to higher neoantigen levels, a more inflamed tumor microenvironment, and improved CPI response. RBM17 is associated with higher ASEs and neoantigen levels, thereby potentiating the efficacy of CPI in BLCA. The established predictive signature, utilizing only two genes, has the potential to streamline clinical applications, providing a cost-effective alternative to expensive genomic, transcriptomic, and biological feature tests.
检查点抑制剂（CPIs）已广泛应用于膀胱癌（BLCA）患者的治疗。然而，剖析反应预测生物标志物仍存在未满足的需求。为了在癌细胞中发现与CPI反应相关的标记基因，我们利用了SCISSOR，整合了单细胞RNA和批量RNA测序数据。收集了来自IMvigor210、UNC - 108和BCAN/HCRN数据集的转录组和临床数据，以评估和验证所鉴定的生物标志物和特征。此外，我们分析了TCGA - BLCA和局部BLCA RNA测序数据，以研究可变剪接事件（ASEs）。在RBM17上调或下调的T24和UMUC3细胞中评估细胞活力。通过SCISSOR分析，我们发现RBM17、TAP1和PSMB8的表达水平与CPI反应显著相关。由于PSMB8与TAP1显示出高度正相关，我们基于RBM17和TAP1的表达谱开发了一个CPI反应评分（CRS）特征。CRS在IMvigor210、UNC - 108和BCAN/HCRN数据集中显示出强大的预测能力，并且与更高的肿瘤突变负担（TMB）、PD - L1表达和独特的基因组特征相关。值得注意的是，RBM17与BLCA患者的临床结局无关，但与体外BLCA细胞增殖呈正相关。同时，RBM17与核心生物学途径中的更高活性相关，包括抗原加工机制、CD8 + T效应细胞、细胞周期、DNA损伤修复、上皮 - 间质转化、组蛋白调节和免疫检查点。此外，高RBM17组显示LumU/Ba/sq亚型富集，但FGFR3改变较少。最后，RBM17显著上调BLCA样本中的ASEs，导致更高的新抗原水平、更具炎症的肿瘤微环境和改善的CPI反应。RBM17与更高的ASEs和新抗原水平相关，从而增强了CPI在BLCA中的疗效。所建立的预测特征仅利用两个基因，有可能简化临床应用，为昂贵的基因组、转录组和生物学特征检测提供一种经济有效的替代方案。
