Hong Shuo, Zhang Yueming, Cao Manming, Lin Anqi, Yang Qi, Zhang Jian, Luo Peng, Guo Linlang
Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Front Cell Dev Biol. 2021 Nov 25;9:762478. doi: 10.3389/fcell.2021.762478. eCollection 2021.
Resistance to immune checkpoint inhibitors (ICIs) has been a massive obstacle to ICI treatment in metastatic urothelial carcinoma (MUC). Recently, increasing evidence indicates the clinical importance of the association between hypoxia and immune status in tumor patients. Therefore, it is necessary to investigate the relationship between hypoxia and prognosis in metastatic urothelial carcinoma. Transcriptomic and clinical data from 348 MUC patients who underwent ICI treatment from a large phase 2 trial (IMvigor210) were investigated in this study. The cohort was randomly divided into two datasets, a training set ( = 213) and a testing set ( = 135). Data of hypoxia-related genes were downloaded from the molecular signatures database (MSigDB), and screened by univariate and multivariate Cox regression analysis to construct a prognosis-predictive model. The robustness of the model was evaluated in two melanoma cohorts. Furthermore, an external validation cohort, the bladder cancer cohort, from the Cancer Genome Atlas (TCGA) database, was t used to explore the mechanism of gene mutation, immune cell infiltration, signaling pathway enrichment, and drug sensitivity. We categorized patients as the high- or low- risk group using a four-gene hypoxia risk model which we constructed. It was found that patients with high-risk scores had significantly worse overall survival (OS) compared with those with low-risk scores. The prognostic model covers 0.71 of the area under the ROC curve in the training set and 0.59 in the testing set, which is better than the survival prediction of MUC patients using the clinical characteristics. Mutation analysis results showed that deletion mutations in RB1, TP53, TSC1 and KDM6A were correlated with hypoxic status. Immune cell infiltration analysis illustrated that the infiltration T cells, B cells, Treg cells, and macrophages was correlated with hypoxia. Functional enrichment analysis revealed that a hypoxic microenvironment activated inflammatory pathways, glucose metabolism pathways, and immune-related pathways. In this investigation, a four-gene hypoxia risk model was developed to evaluate the degree of hypoxia and prognosis of ICI treatment, which showed a promising clinical prediction value in MUC. Furthermore, the hypoxia risk model revealed a close relationship between hypoxia and the tumor immune microenvironment.
对免疫检查点抑制剂（ICI）产生耐药性一直是转移性尿路上皮癌（MUC）中ICI治疗的巨大障碍。最近，越来越多的证据表明缺氧与肿瘤患者免疫状态之间的关联具有临床重要性。因此，有必要研究转移性尿路上皮癌中缺氧与预后的关系。本研究调查了来自一项大型2期试验（IMvigor210）中接受ICI治疗的348例MUC患者的转录组和临床数据。该队列被随机分为两个数据集，一个训练集（= 213）和一个测试集（= 135）。从分子特征数据库（MSigDB）下载缺氧相关基因的数据，并通过单变量和多变量Cox回归分析进行筛选，以构建预后预测模型。在两个黑色素瘤队列中评估了该模型的稳健性。此外，还使用来自癌症基因组图谱（TCGA）数据库的外部验证队列——膀胱癌队列，来探索基因突变、免疫细胞浸润、信号通路富集和药物敏感性的机制。我们使用构建的四基因缺氧风险模型将患者分为高风险或低风险组。结果发现，高风险评分的患者与低风险评分的患者相比，总生存期（OS）明显更差。该预后模型在训练集中的ROC曲线下面积为0.71，在测试集中为0.59，优于使用临床特征对MUC患者的生存预测。突变分析结果表明，RB1、TP53、TSC1和KDM6A的缺失突变与缺氧状态相关。免疫细胞浸润分析表明，T细胞、B细胞、调节性T细胞和巨噬细胞的浸润与缺氧相关。功能富集分析显示，缺氧微环境激活了炎症通路、糖代谢通路和免疫相关通路。在本研究中，开发了一种四基因缺氧风险模型来评估ICI治疗的缺氧程度和预后，该模型在MUC中显示出有前景的临床预测价值。此外，缺氧风险模型揭示了缺氧与肿瘤免疫微环境之间的密切关系。
