Ferroptosis Regulator Modification Patterns and Tumor Microenvironment Immune Infiltration Characterization in Hepatocellular Carcinoma.
Ferroptosis Regulator Modification Patterns and Tumor Microenvironment Immune Infiltration Characterization in Hepatocellular Carcinoma.
复制标题
肝细胞癌中的铁质调节器修饰模式和肿瘤微环境的免疫浸润表征。
DOI：
10.3389/fmolb.2022.807502
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发表时间：
2022
影响因子：
5
通讯作者：
Wang CG
中科院分区：
文献类型：
--
作者：
Liu DL;Wu MY;Zhang TN;Wang CG
越来越多的研究强调了铁凋亡修饰在肿瘤进展中的生物学意义，但铁凋亡修饰模式是否在肝细胞癌（HCC）的肿瘤微环境（TME）免疫细胞浸润中具有潜在作用尚不清楚。在这项研究中，我们评估了51个铁凋亡调控因子，并进行了一致性聚类算法，以确定肝癌中铁凋亡修饰模式和铁凋亡相关基因签名。基因集变异分析（GSVA），探讨不同的铁凋亡修饰模式的生物分子变异。进行单样本基因集富集分析（ssGSEA）算法以定量各种免疫细胞亚群的相对浸润水平。使用主成分分析（PCA）算法来构建铁凋亡Sig评分，以量化具有免疫应答的个体肿瘤的铁凋亡修饰模式。鉴定了三种不同的铁凋亡修饰模式。GSVA富集分析表明，三个铁凋亡修饰亚群在不同的代谢途径中富集。ssGSEA分析确定24个免疫浸润细胞中的19个在三种不同的铁凋亡模式中具有显著差异。构建了一个91-ferroptosis基因标签，将患者分为两个ferroptosis Sig评分组。与低分数组相比，高分数组患者的生存时间显著延长（p <0.0001）。一个免疫治疗队列证实，具有更高的ferroposisSig评分的患者确定了显着的治疗优势和临床获益。受试者工作特征（ROC）曲线分析证实了铁尿症Sig评分对抗PD/L1免疫治疗的预测能力。我们的研究表明，铁凋亡修饰在TME异质性和复杂性中起着重要作用。评价个体肿瘤的铁凋亡修饰模式，可以加深对TME浸润特点的认识，指导临床更有效的免疫治疗策略。
Accumulating studies have highlighted the biologic significances of ferroptosis modification in tumor progression, but little is known whether ferroptosis modification patterns have potential roles in tumor microenvironment (TME) immune cell infiltration of hepatocellular carcinoma (HCC). In this study, we evaluated 51 ferroptosis regulators and performed consensus clustering algorithm to determine ferroptosis modification patterns and the ferroptosis related gene signature in HCC. Gene set variation analysis (GSVA) was employed to explore biological molecular variations in distinct ferroptosis modification patterns. Single sample gene set enrichment analysis (ssGSEA) algorithm was performed to quantify the relative infiltration levels of various immune cell subsets. Principal component analysis (PCA) algorithm was used to construct the ferroptosisSig score to quantify ferroptosis modification patterns of individual tumors with immune responses. Three distinct ferroptosis modification patterns were identified. GSVA enrichment analysis indicated that three ferroptosis modification subgroups were enriched in different metabolic pathways. ssGSEA analysis determined that 19 of 24 immune infiltrating cells had significant differences in three distinct ferroptosis patterns. A 91-ferroptosis gene signature was constructed to stratify patients into two ferroptosisSig score groups. Patients in the higher ferroptosisSig score were characterized by significantly prolonged survival time compared with patients in the lower ferroptosisSig score group (p < .0001). An immunotherapy cohort confirmed patients with higher ferroptosisSig score determined significant therapeutic advantages and clinical benefits. Receiver operating characteristic (ROC) curve analysis confirmed the predictive capacity of anti-PD/L1 immunotherapy by ferroptosisSig score. Our study indicated the ferroptosis modification played a significant role in TME heterogeneity and complexity. Evaluating the ferroptosis modification pattern of individual tumor could strengthen our cognition of TME infiltration characteristics and guide more effective clinic immunotherapy strategies.