Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis.
Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis.
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基于WGCNA分析鉴定与LUAD免疫治疗耐药相关的关键通路和基因
DOI：
10.3389/fonc.2021.814014
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发表时间：
2021
影响因子：
4.7
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Yu W;Liu F;Lei Q;Wu P;Yang L;Zhang Y
免疫治疗耐药性是免疫检查点抑制剂（ICI）在肺腺癌（LUAD）患者中应用的主要障碍。尽管最近的研究发现了几种导致免疫治疗耐药的机制和潜在基因，但仍然缺乏解决这一问题的方法。肿瘤免疫功能障碍和排除（TIDE）算法是一种新开发的计算 ICI 抵抗的潜在调节因子和指标的方法。在本文中，我们结合 TIDE 和加权基因共表达网络分析 (WGCNA)，利用 LUAD 患者的癌症基因组图谱 (TCGA) 数据集筛选与免疫治疗耐药高度相关的潜在模块和枢纽基因。我们鉴定了 45 个基因共表达模块，其中粉色模块与 TIDE 评分和其他免疫抑制特征最相关。在考虑免疫治疗耐药的潜在因素后，我们发现粉红色模块也与癌症干性高度相关。进一步分析显示细胞外基质（ECM）中丰富的免疫抑制细胞、免疫治疗耐药指标以及粉红色模块中常见的癌症相关信号通路。与正常肺组织相比，粉红色模块中的 7 个 hub 基因在肿瘤组织中显着上调，并且与 LUAD 患者的不良生存相关。其中，THY1是与TIDE评分最相关的基因，该基因与抑制性免疫状态高度相关，并且在晚期患者中表现出强烈表达。免疫组织化学 (IHC) 结果表明，接受 PD-1 单克隆抗体 (mAb) 治疗的 LUAD 患者的进展性疾病 (PD) 组中 THY1 水平较高，并且与 SOX9 呈正相关。总的来说，我们发现 THY1 可能是预测 ICI 效率的关键生物标志物，也是避免肿瘤免疫治疗耐药的潜在靶点。
Immunotherapy resistance is a major barrier in the application of immune checkpoint inhibitors (ICI) in lung adenocarcinoma (LUAD) patients. Although recent studies have found several mechanisms and potential genes responsible for immunotherapy resistance, ways to solve this problem are still lacking. Tumor immune dysfunction and exclusion (TIDE) algorithm is a newly developed method to calculate potential regulators and indicators of ICI resistance. In this article, we combined TIDE and weighted gene co-expression network analysis (WGCNA) to screen potential modules and hub genes that are highly associated with immunotherapy resistance using the Cancer Genome Atlas (TCGA) dataset of LUAD patients. We identified 45 gene co-expression modules, and the pink module was most correlated with TIDE score and other immunosuppressive features. After considering the potential factors in immunotherapy resistance, we found that the pink module was also highly related to cancer stemness. Further analysis showed enriched immunosuppressive cells in the extracellular matrix (ECM), immunotherapy resistance indicators, and common cancer-related signaling pathways in the pink module. Seven hub genes in the pink module were shown to be significantly upregulated in tumor tissues compared with normal lung tissue, and were related to poor survival of LUAD patients. Among them, THY1 was the gene most associated with TIDE score, a gene highly related to suppressive immune states, and was shown to be strongly expressed in late-stage patients. Immunohistochemistry (IHC) results demonstrated that THY1 level was higher in the progressive disease (PD) group of LUAD patients receiving a PD-1 monoclonal antibody (mAb) and positively correlated with SOX9. Collectively, we identified that THY1 could be a critical biomarker in predicting ICI efficiency and a potential target for avoiding tumor immunotherapy resistance.
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WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
PD-L1通过维持PI3K/AKT途径激活来促进乳腺癌干细胞中的Oct4和Nanog表达。
影响因子：
6.4
作者：
Almozyan S;Colak D;Mansour F;Alaiya A;Al-Harazi O;Qattan A;Al-Mohanna F;Al-Alwan M;Ghebeh H
通讯作者：
Ghebeh H
DOI：
10.1158/1078-0432.ccr-15-2665
发表时间：
2016-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Lee Y;Shin JH;Longmire M;Wang H;Kohrt HE;Chang HY;Sunwoo JB
通讯作者：
Sunwoo JB
影响因子：
3.7
作者：
Irvin DK;Jouanneau E;Duvall G;Zhang XX;Zhai Y;Sarayba D;Seksenyan A;Panwar A;Black KL;Wheeler CJ
通讯作者：
Wheeler CJ
影响因子：
14.9
作者：
Almeida LG;Sakabe NJ;deOliveira AR;Silva MC;Mundstein AS;Cohen T;Chen YT;Chua R;Gurung S;Gnjatic S;Jungbluth AA;Caballero OL;Bairoch A;Kiesler E;White SL;Simpson AJ;Old LJ;Camargo AA;Vasconcelos AT
通讯作者：
Vasconcelos AT