Table4_Immune-related gene risk score predicting the effect of immunotherapy and prognosis in bladder cancer patients.XLS

Background: Immune checkpoint inhibitor therapy has changed the treatment model of metastatic bladder cancer. However, only approximately 20% of patients benefit from this therapy, and robust biomarkers to predict the effect of immunotherapy are still lacking. In this study, we aimed to investigate whether immune-related genes could be indicators for the prognosis of bladder cancer patients and the effect of immunotherapy.Methods: Based on bladder cancer dataset from the Cancer Genome Atlas (TCGA) and GSE48075, 22 immune microenvironment-related cells were identified by CIBERSORT. After performing a series of bioinformatic and machine learning approaches, we identified distinct tumor microenvironment clusters and three bladder cancer specific immune-related genes (EGFR, OAS1 and MST1R). Then, we constructed immune-related gene risk score (IRGRS) by using the Cox regression method and validated it with the IMvigor210 dataset.Results: IRGRS-high patients had a worse overall survival than IRGRS-low patients, which was consistent with the result in the IMvigor210 dataset. Comprehensive analysis shows that patients with high IRGRS scores are mainly enriched in basal/squamous type (Ba/Sq), and tumor metabolism-related pathways are more Active, with higher TP53 and RB1 gene mutation rates, lower CD4+/CD8+ T cell infiltration, higher M0 macrophage infiltration, and lower immunotherapy efficacy. In contrast, Patients with low IRGRS scores are mainly enriched in the luminal papillary type (LumP), which is associated with the activation of IL-17 and TNF signaling pathways, higher mutation rates of FGFR3 and CDKN1A genes, higher CD4+/CD8+ T cell infiltration content, and The level of M0 macrophage infiltration was relatively low, and the immunotherapy was more probably effective.Conclusion: Our study constructed an IRGRS for bladder cancer and clarified the immune and molecular characteristics of IRGRS-defined subgroups of bladder cancer to investigate the association between IRGRS and its potential implications for prognosis and immunotherapy.

背景：免疫检查点抑制剂疗法已改变转移性膀胱癌的治疗模式。然而，仅有大约20%的患者能从该疗法中获益，而预测免疫疗法效果的稳健生物标志物仍显不足。本研究旨在探讨免疫相关基因是否可作为膀胱癌患者预后及免疫疗法效果的指标。方法：基于癌症基因组图谱（TCGA）和GSE48075的膀胱癌数据集，通过CIBERSORT技术鉴定了22种免疫微环境相关细胞。经过一系列生物信息学和机器学习方法的处理，我们确定了独特的肿瘤微环境聚类以及三种膀胱癌特异性免疫相关基因（EGFR、OAS1和MST1R）。随后，我们利用Cox回归方法构建了免疫相关基因风险评分（IRGRS），并通过IMvigor210数据集进行验证。结果：IRGRS高风险患者的总生存率低于IRGRS低风险患者，这与IMvigor210数据集中的结果一致。综合分析显示，IRGRS高风险患者主要富集于基底层/鳞状细胞型（Ba/Sq），肿瘤代谢相关通路活性更高，TP53和RB1基因突变率更高，CD4+/CD8+ T细胞浸润较低，M0巨噬细胞浸润较高，免疫疗法疗效较低。相反，IRGRS低风险患者主要富集于管状乳头状型（LumP），与IL-17和TNF信号通路激活有关，FGFR3和CDKN1A基因突变率更高，CD4+/CD8+ T细胞浸润含量更高，M0巨噬细胞浸润水平相对较低，免疫疗法更有可能有效。结论：本研究构建了膀胱癌的IRGRS，并阐明了IRGRS定义的膀胱癌亚组的免疫和分子特征，以研究IRGRS与其预后及免疫疗法潜在影响的关联。