基于铁死亡基因的恶性胸膜间皮瘤风险预测模型构建及其肿瘤免疫微环境研究  

Construction of risk prognosis model for malignant pleural mesothelioma based on ferroptosis gene and study on tumor immune microenvironment

作　　者：陈梓林 杨思海 马鸿辉 王咏仪 叶晓莹 黄浩宇 王雯倩 CHEN Zilin;YANG Sihai;MA Honghui;WANG Yongyi;YE Xiaoying;HUANG Haoyu;WANG Wenqian(The Second Affiliated Hospital of Guangzhou Medical University,Guangzhou 510260,China)

机构地区：[1]广州医科大学附属第二医院,广州510260

出　　处：《中国免疫学杂志》2024年第5期961-969,共9页Chinese Journal of Immunology

基　　金：广州市科技计划项目(202102020152);广州市卫生健康科技项目(20221A011084);广州医科大学第二临床学院大学生科技创新重点项目(S2022A020)。

摘　　要：目的:筛选恶性胸膜间皮瘤(MPM)预后相关的铁死亡基因,探索铁死亡与肿瘤免疫微环境的联系,为MPM患者的靶向及免疫治疗提供新的视角。方法:分析GEO数据集中MPM肿瘤组和正常组的差异表达基因(DEGs),与铁死亡基因取交集得到MPM中铁死亡相关的DEGs(DE-FRGs);进行GO、KEGG功能富集和蛋白-蛋白互作(PPI)等分析明确DE-FRGs主要参与的信号通路;通过单因素COX分析鉴定出预后相关的铁死亡基因,LASSO回归分析筛选建立风险预测模型的最佳DEFRGs,并通过多因素COX分析建立基于最佳DE-FRGs的风险预测模型,对模型的预测效果进行一系列验证。最后通过CIBERSORT等算法对模型进行肿瘤免疫细胞浸润分析及免疫微环境评价。结果:筛选出24个预后相关的DE-FRGs,主要富集于铁死亡、转录调控和对无机物的反应,建立并验证了1个基于5个铁死亡相关基因(ALDH3A2、CAV1、HRAS、CDCA3、RRM2)的MPM风险预测模型,模型中高风险组CD8+T细胞、巨噬细胞比例较高,而B淋巴细胞占比较低。此外,免疫检查点PD-1、CTLA-4及其配体在高风险组中有更高的表达状态。结论:建立了基于5个铁死亡相关基因的MPM风险预测模型,并明确了模型中的免疫状态。为MPM的靶向及免疫治疗提供了一定的研究基础,该模型在MPM中的预测能力需要临床上进一步验证,以更好地预测疾病分层和治疗管理。Objective:To screen ferroptosis genes related to prognosis of malignant pleural mesothelioma(MPM),explore the relationship between ferroptosis and tumor immune microenvironment and provide a new perspective for targeting and immunotherapy of MPM patients.Methods:The differentially expressed genes(DEGs)in MPM tumor group and normal group were analyzed in GEO database;intersection of DEGs and ferroptosis genes to obtain differentially expressed ferroptosis-related genes(DE-FRGs).GO,KEGG function enrichment and protein protein interaction(PPI)were used to identify the signal pathways mainly involved by DEFRGs.The prognosis related ferroptosis genes were identified by univariate COX analysis.LASSO regression analysis was used to screen the best DE-FRGs for establishing the risk prediction model,and a risk prognosis model based on the best DE-FRGs was established by multivariate cox analysis to verify the prediction effect of the model.Finally,CIBERSORT and other algorithms were used to analyze tumor immune cell infiltration and evaluate immune microenvironment.Results:Twenty-four prognosis related DE-FRGs were screened,which were mainly concentrated in ferroptosis,transcriptional regulation and response to inorganic substances.A MPM risk prediction model based on five ferroptosis-related genes(ALDH3A2,CAV1,HRAS,CDCA3 and RRM2)was established and validated.In the model,the proportion of CD8+T cells and macrophages in high-risk group were higher,while the proportion of B lymphocytes was lower.In addition,PD-1,CTLA-4 and their ligands at immune checkpoint had higher expression status in high-risk group.Conclusion:The MPM risk prediction model based on five ferroptosis-related genes is established,and the immune status in the model is clarified.It provides a certain research basis for targeting and immunotherapy of MPM.The predictive ability of this model in MPM needs to be further verified in clinical practice to better predict disease stratification and treatment management.

关 键 词：铁死亡 恶性胸膜间皮瘤 风险预测模型 肿瘤免疫细胞浸润 

分 类 号：R734.3[医药卫生—肿瘤]