Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, 9 DongDan Santiao, Beijing, 100730, China.
Eur J Med Res. 2024 Feb 9;29(1):112. doi: 10.1186/s40001-024-01688-9.
Bladder cancer is a common malignancy of the urinary system, and the survival rate and recurrence rate of patients with muscular aggressive (MIBC) bladder cancer are not ideal. Hypoxia is a pathological process in which cells acquire special characteristics to adapt to anoxic environment, which can directly affect the proliferation, invasion and immune response of bladder cancer cells. Understanding the exact effects of hypoxia and immune-related genes in BLCA is helpful for early assessment of the prognosis of BLCA. However, the prognostic model of BLCA based on hypoxia and immune-related genes has not been reported.
Hypoxia and immune cell have important role in the prognosis of bladder cancer (BLCA). The aim of this study was to investigate whether hypoxia and immune related genes could be a novel tools to predict the overall survival and immunotherapy of BLCA patients.
First, we downloaded transcriptomic data and clinical information of BLCA patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A combined hypoxia and immune signature was then constructed on the basis of the training cohort via least absolute shrinkage and selection operator (LASSO) analysis and validated in test cohort. Afterwards, Kaplan-Meier curves, univariate and multivariate Cox and subgroup analysis were employed to assess the accuracy of our signature. Immune cell infiltration, checkpoint and the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm were used to investigate the immune environment and immunotherapy of BLCA patients. Furthermore, we confirmed the role of TFRC in bladder cancer cell lines T24 and UMUC-3 through cell experiments.
A combined hypoxia and immune signature containing 8 genes were successfully established. High-risk group in both training and test cohorts had significantly poorer OS than low-risk group. Univariate and multivariate Cox analysis indicated our signature could be regarded as an independent prognostic factor. Different checkpoint was differently expressed between two groups, including CTLA4, HAVCR2, LAG3, PD-L1 and PDCD1. TIDE analysis indicated high-risk patients had poor response to immunotherapy and easier to have immune escape. The drug sensitivity analysis showed that high-risk group patients were more potentially sensitive to many drugs. Meanwhile, TFRC could inhibit the proliferation and invasion ability of T24 and UMUC-3 cells.
A combined hypoxia and immune-related gene could be a novel predictive model for OS and immunotherapy estimation of BLCA patients and TFRC could be used as a potential therapeutic target in the future.
膀胱癌是泌尿系统常见的恶性肿瘤，肌层浸润性膀胱癌（MIBC）患者的生存率和复发率不理想。缺氧是细胞获得适应缺氧环境特殊特征的病理过程，可直接影响膀胱癌细胞的增殖、侵袭和免疫反应。了解 BLCA 中确切的缺氧和免疫相关基因的作用有助于早期评估 BLCA 的预后。然而，基于缺氧和免疫相关基因的 BLCA 预后模型尚未报道。
缺氧和免疫细胞在膀胱癌（BLCA）的预后中起着重要作用。本研究旨在探讨缺氧和免疫相关基因是否可以成为预测 BLCA 患者总生存期和免疫治疗的新工具。
首先，我们从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）下载了 BLCA 患者的转录组数据和临床信息。然后，我们通过最小绝对收缩和选择算子（LASSO）分析，在训练队列的基础上构建了一个联合缺氧和免疫特征，并在测试队列中进行了验证。随后，我们采用 Kaplan-Meier 曲线、单因素和多因素 Cox 分析以及亚组分析来评估我们的特征的准确性。我们还使用免疫细胞浸润、检查点和肿瘤免疫功能障碍和排除（TIDE）算法来研究 BLCA 患者的免疫环境和免疫治疗。此外，我们通过细胞实验证实了 TFRC 在膀胱癌细胞系 T24 和 UMUC-3 中的作用。
成功建立了一个包含 8 个基因的联合缺氧和免疫特征。训练和测试队列中的高风险组的 OS 明显低于低风险组。单因素和多因素 Cox 分析表明，我们的特征可以作为独立的预后因素。两组之间不同的检查点表达不同，包括 CTLA4、HAVCR2、LAG3、PD-L1 和 PDCD1。TIDE 分析表明，高危患者对免疫治疗的反应较差，更容易发生免疫逃逸。药物敏感性分析表明，高危组患者对许多药物更具潜在敏感性。同时，TFRC 可以抑制 T24 和 UMUC-3 细胞的增殖和侵袭能力。
联合缺氧和免疫相关基因可以作为预测 BLCA 患者 OS 和免疫治疗评估的新型预测模型，TFRC 可能成为未来的潜在治疗靶点。
