Zou Yuantao, Yuan Gangjun, Tan Xingliang, Luo Sihao, Yang Cong, Tang Yi, Wang Yanjun, Yao Kai
Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
State Key Laboratory of Oncology in Southern China, Guangzhou, China.
Front Genet. 2022 Oct 4;13:1011390. doi: 10.3389/fgene.2022.1011390. eCollection 2022.
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. 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. 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. 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.
免疫检查点抑制剂疗法改变了转移性膀胱癌的治疗模式。然而，只有约20%的患者能从该疗法中获益，目前仍缺乏能可靠预测免疫治疗效果的生物标志物。在本研究中，我们旨在探究免疫相关基因是否可作为膀胱癌患者预后及免疫治疗效果的指标。基于癌症基因组图谱（TCGA）和GSE48075的膀胱癌数据集，通过CIBERSORT鉴定出22种免疫微环境相关细胞。在进行了一系列生物信息学和机器学习方法后，我们识别出不同的肿瘤微环境簇以及三个膀胱癌特异性免疫相关基因（EGFR、OAS1和MST1R）。然后，我们使用Cox回归方法构建了免疫相关基因风险评分（IRGRS），并在IMvigor210数据集上进行了验证。IRGRS高的患者总生存期比IRGRS低的患者更差，这与IMvigor210数据集的结果一致。综合分析表明，IRGRS评分高的患者主要富集于基底/鳞状型（Ba/Sq），肿瘤代谢相关通路更活跃，TP53和RB1基因突变率更高，CD4+/CD8+ T细胞浸润更低，M0巨噬细胞浸润更高，免疫治疗疗效更低。相比之下，IRGRS评分低的患者主要富集于管腔乳头状型（LumP），这与IL-17和TNF信号通路的激活、FGFR3和CDKN1A基因的更高突变率、更高的CD4+/CD8+ T细胞浸润含量以及相对较低的M0巨噬细胞浸润水平相关，免疫治疗更可能有效。我们的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与其对预后和免疫治疗的潜在影响之间的关联。
