Wang Liang, Ge Xiangwei, Zhang Zifeng, Ye Yating, Zhou Ziyi, Li Manhong, Yan Hongxiang, Wu Lei, Bai Qian, Li Jipeng, Zhu Jun, Wang Yusheng
Department of Ophthalmology Eye Institute of Chinese PLA Xijing Hospital Fourth Military Medical University, Xi'an, China.
Department of Ophthalmology The Northern Theater Air Force Hospital, Shenyang, China.
Front Genet. 2021 Oct 21;12:682082. doi: 10.3389/fgene.2021.682082. eCollection 2021.
Immune checkpoint blockers (ICBs) are increasingly being used to treat patients with advanced hepatocellular carcinoma (HCC), but only a third of these patients are sensitive to ICBs. Emerging evidence suggests that ferroptosis could be a novel target for antitumor treatment, and combined treatment with ferroptosis inducers might enhance sensitivity to immunotherapy. However, there is a lack of information on the crosstalk between ferroptosis-related lncRNAs and anti-tumor immunity. Therefore, we aim to explore prognostic value of ferroptosis-related lncRNAs and clarify potential role in ICBs of HCC. We obtained mRNA and lncRNA expression data from two independent cohorts (TCGA and GEO database). Univariate Cox, the least absolute shrinkage and selection operator (Lasso) algorithm and multivariate Cox analysis were used to construct a lncRNA signature, which was evaluated using the area under the receiver operating characteristic curve (AUC) and Kaplan-Meier curves. Tumor-infiltrating cell (TIC) profiling and the tumor immune dysfunction and exclusion (TIDE) algorithm were used to validate the signature model and immunotherapy. Finally, we adopted RT-PCR assay to evaluate the differential expression of lncRNAs in HCC tissues in our hospital. The ferroptosis-related lncRNA signature included five lncRNAs, most of which were positively correlated with clinical stage and grade. The signature could stratify patients into two risk groups, with the high-risk group associated with a shorter overall survival (OS, < 0.05) in TCGA-LIHC and GSE76427. Besides, the AUCs of the 1-, 3-, and 5-years OS were 0.772, 0.707, and 0.666, respectively. Gene set enrichment analysis (GESA) of lncRNAs revealed enrichment of oncogenic and immune-related pathways. The TIC profiling indicated a close correlation between the signature and immune cells. Furthermore, the high-risk group had a better response to immunotherapy than low-risk group. RT-PCR demonstrated these five lncRNAs were upregulated in cancerous tissue than normal tissues. The ferroptosis-related lncRNA signature could accurately predict the OS of HCC patients and may serve as an independent clinical factor for patients' outcomes. Ferroptosis-related lncRNAs may remodel the tumor microenvironment (TME) and affect the anti-cancer ability of ICBs, and therefore, could potentially act as an indicator for the response to immunotherapy in HCC.
免疫检查点阻断剂（ICBs）越来越多地用于治疗晚期肝细胞癌（HCC）患者，但这些患者中只有三分之一对ICBs敏感。新出现的证据表明，铁死亡可能是抗肿瘤治疗的一个新靶点，与铁死亡诱导剂联合治疗可能会增强对免疫治疗的敏感性。然而，关于铁死亡相关lncRNAs与抗肿瘤免疫之间的相互作用的信息却很少。因此，我们旨在探讨铁死亡相关lncRNAs的预后价值，并阐明其在HCC的ICBs中的潜在作用。我们从两个独立队列（TCGA和GEO数据库）获得了mRNA和lncRNA表达数据。使用单因素Cox、最小绝对收缩和选择算子（Lasso）算法以及多因素Cox分析来构建lncRNA特征，并用受试者工作特征曲线（AUC）下面积和Kaplan-Meier曲线对其进行评估。采用肿瘤浸润细胞（TIC）分析和肿瘤免疫功能障碍与排除（TIDE）算法来验证特征模型和免疫治疗。最后，我们采用RT-PCR检测来评估我院HCC组织中lncRNAs的差异表达。铁死亡相关lncRNA特征包括5个lncRNAs，其中大多数与临床分期和分级呈正相关。该特征可将患者分为两个风险组，在TCGA-LIHC和GSE76427中，高风险组的总生存期（OS）较短（P<0.05）。此外，1年、3年和5年OS的AUC分别为0.772、0.707和0.666。lncRNAs的基因集富集分析（GESA）显示致癌和免疫相关途径的富集。TIC分析表明该特征与免疫细胞密切相关。此外，高风险组对免疫治疗的反应优于低风险组。RT-PCR显示这5个lncRNAs在癌组织中比正常组织中上调。铁死亡相关lncRNA特征可以准确预测HCC患者的OS，并可能作为患者预后的独立临床因素。铁死亡相关lncRNAs可能重塑肿瘤微环境（TME）并影响ICBs的抗癌能力，因此，有可能作为HCC免疫治疗反应的指标。
