Comprehensive Analysis of Immune Implication and Prognostic Value of IFI44L in Non-Small Cell Lung Cancer.
Comprehensive Analysis of Immune Implication and Prognostic Value of IFI44L in Non-Small Cell Lung Cancer.
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IFI44L对非小细胞肺癌的免疫意义及预后价值综合分析
DOI：
10.3389/fonc.2021.798425
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发表时间：
2021
影响因子：
4.7
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Zeng Y;Zhang Z;Chen H;Fan J;Yuan W;Li J;Zhou S;Liu W
干扰素诱导蛋白44样（IFI 44 L）是一种I型干扰素刺激基因（ISG），参与先天性免疫过程，在多种肿瘤中具有抑癌作用。然而，其对肺癌的免疫影响仍不清楚。在这里，我们通过生物信息学方法在癌症基因组图谱（TCGA）肺癌队列中系统地分析了IFI 44 L与多种肿瘤浸润免疫细胞（TIIC）和免疫调节剂的免疫相关性。然后，选择IFI 44 L相关免疫调节剂分别构建肺腺癌（LUAD）队列和肺鳞状细胞癌（LUSC）队列的预后特征。应用一致性指数和时间依赖性受试者工作特征（ROC）曲线评估预后特征。GSE 72094和GSE 50081分别用于验证TCGA-LUAD签名和TCGA-LUSC签名。根据LUAD队列的风险评分和临床特征建立列线图。最后，在真实世界队列和体外实验中验证了IFI 44 L的预后价值和生物学功能。结果表明，IFI 44 L与LUAD和LUSC样品中的TIIC均呈显著相关。功能富集分析表明，IFI 44 L可能参与多种肿瘤/免疫相关通路，包括JAK/STAT信号通路和NF-κB信号通路。在TCGA-LUAD队列中，共有44种免疫调节剂与IFI 44 L存在明显相关性，并构建了一个稳健的10种免疫调节剂特征。高风险组患者的预后比低风险组差。值得注意的是，在GSE 72094中成功确认了风险特征。多变量考克斯回归表明，风险签名可以作为独立的预后因素在两个TCGA-LUAD和GSE 72094队列。此外，在TCGA-LUSC队列中建立了17种免疫调节剂特征，并通过分析显示了相似的结果。与风险特征和其他临床特征相比，诺模图在预测TCGA-LUAD患者的总生存期（OS）结局方面表现出良好的准确性，1年时曲线下面积值为0.782，3年时为0.825，5年时为0.792。最后，组织芯片分析表明，IFI 44 L的高表达与病理分期呈相反的关系（p = 0.016），并且在肺癌患者中具有更好的预后（p = 0.024）。功能实验发现IFI 44 L过表达显著抑制LUAD和LUSC细胞的增殖、迁移和侵袭; RT-qPCR实验验证了SPC-A-1和NCI-H520细胞中IFI 44 L的表达水平与多种免疫调节剂之间的相关性。总之，我们的研究强调了IFI 44 L与肿瘤免疫浸润相关，并提供了IFI 44 L的免疫含义的信息，这表明IFI 44 L具有潜在的临床免疫学价值，并且所提出的诺模图是一种有希望的非小细胞肺癌患者的生物标志物。
Interferon-induced protein 44-like (IFI44L), a type I interferon-stimulated gene (ISG), has been reported to be involved in innate immune processes and to act as a tumor suppressor in several cancers. However, its immune implication on lung cancer remains unclear. Here, we systemically analyzed the immune association of IFI44L with multiple tumor-infiltrating immune cells (TIICs) and immunomodulators through bioinformatics methods in The Cancer Genome Atlas (TCGA) lung cancer cohorts. Then, the IFI44L-related immunomodulators were selected to construct the prognostic signatures in the lung adenocarcinoma (LUAD) cohort and the lung squamous cell carcinoma (LUSC) cohort, respectively. Concordance index and time-dependent receiver operating characteristics (ROC) curves were applied to evaluate the prognostic signatures. GSE72094 and GSE50081 were used to validate the TCGA-LUAD signature and TCGA-LUSC signature, respectively. A nomogram was established by risk score and clinical features in the LUAD cohort. Finally, the prognostic value and biological function of IFI44L were verified in a real-world cohort and in vitro experiments. The results indicated that IFI44L showed significant correlation with TIICs in LUAD and LUSC samples. Functional enrichment analysis showed that IFI44L may participate in various cancer/immune-related pathways, including JAK/STAT signaling pathway and NF-κB signaling pathway. A total of 44 immunomodulators presented obvious association with IFI44L in the TCGA-LUAD cohort and a robust 10-immunomodulator signature was constructed. Patients in the higher-risk group presented worse prognosis than those in the lower-risk group. Notably, the risk signature was successfully validated in GSE72094. Multivariate Cox regression suggested that the risk signature could act as independent prognostic factors in both TCGA-LUAD and GSE72094 cohorts. Besides, a 17-immunomodulator signature was established in the TCGA-LUSC cohort and similar results were presented through analysis. The nomogram exhibited good accuracy in predicting overall survival (OS) outcome among TCGA-LUAD patients than the risk signature and other clinical features, with the area under curve values being 0.782 at 1 year, 0.825 at 3 years, and 0.792 at 5 years. Finally, tissue microarray analysis indicated that higher expression of IFI44L presented opposite relationship with pathological stage (p = 0.016) and a better outcome among lung cancer patients (p = 0.024). Functional experiments found that IFI44L overexpression significantly inhibited the proliferation, migration, and invasion in LUAD and LUSC cells; RT-qPCR experiments verified the correlation between the expression level of IFI44L with multiple immunomodulators in SPC-A-1 and NCI-H520 cells. In conclusion, our research highlighted that IFI44L is associated with tumor immune infiltration and provided information on IFI44L’s immune implication, which indicates that IFI44L has potential clinical immunotherapeutic value and the proposed nomogram is a promising biomarker for non-small cell lung cancer patients.
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影响因子：
4.7
作者：
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通讯作者：
Gomez-Chiarri, Marta
影响因子：
2.9
作者：
Liu D;Huang Y;Zhang L;Liang DN;Li L
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作者：
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影响因子：
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作者：
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通讯作者：
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IFI44L 表达受 IRF-1 和 HIV-1 调节
影响因子：
2.6
作者：
Li Y;Zhang J;Wang C;Qiao W;Li Y;Tan J
通讯作者：
Tan J