Unveiling Immunotherapy Evasion in Lung Cancer: The Role of Fanconi Anemia and Stemness Genes in Shaping an Immunosuppressive Microenvironment

IF 3.5 4区医学 Q2 CHEMISTRY, MEDICINAL

Drug Development Research Pub Date : 2024-11-21 DOI:10.1002/ddr.70020

Haixia Wu, Yilin Yu, Hailun Huang, Gen Lin, Wei Wang, Jianyuan Huang, Zhaojun Yu, Deju Ye, Wu Chi, Xing Lin

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Abstract

The study aimed to investigate the fanconi anemia (FA)-related and stemness-related genes in lung cancer (LC) patients. Firstly, we identified stemness-related genes through weighted gene co-expression network analysis combined with TCGA database. Further combined stemness-related genes with FA-related genes to screen for prognostic-related genes. Risk score was constructed from the screened genes and comprehensive bioinformatics analyses were performed. Finally, single-cell data and in vitro experiment were used to validate our results. We screened a total of eight genes to construct a risk score. The risk score was an independent prognostic factor for LC. The validation results of multiple GEO databases were consistent with our results. Functional and pathway enrichment analysis showed that risk score was associated with cell cycle, DNA replication, DNA damage repair, and immune-related pathways. The results showed to be related to the stem cell self-renewal and proliferation. Besides, we also found that patients with higher risk scores had lower immune activity and function, and the effectiveness of immunotherapy might be poorer, with a higher rate of immune escape. Finally, our results revealed that SLC2A1 had the highest correlation with B cells in single-cell data analysis, and we validated its correlation with B cells and its expression with FA-related genes, tumor invasiveness, stemness, and drug sensitivity. Our research constructed a risk score based on FA-related and tumor stemness-related specific genes. In addition to accurately predicting the prognosis of patients with LC, the risk score may also serve as an innovative and viable predictor of immunotherapy response.

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揭示肺癌的免疫疗法规避：范可尼贫血症和干性基因在形成免疫抑制性微环境中的作用

该研究旨在调查肺癌（LC）患者的范可尼贫血症（FA）相关基因和干性相关基因。首先，我们结合TCGA数据库，通过加权基因共表达网络分析确定了干性相关基因。进一步将干细胞相关基因与FA相关基因相结合，筛选出预后相关基因。根据筛选出的基因构建风险评分，并进行综合生物信息学分析。最后，利用单细胞数据和体外实验验证了我们的结果。我们共筛选了八个基因来构建风险评分。该风险评分是 LC 的一个独立预后因素。多个 GEO 数据库的验证结果与我们的结果一致。功能和通路富集分析表明，风险评分与细胞周期、DNA复制、DNA损伤修复和免疫相关通路有关。结果显示与干细胞自我更新和增殖有关。此外，我们还发现，风险评分较高的患者免疫活性和功能较低，免疫治疗的效果可能较差，免疫逃逸率较高。最后，我们的研究结果显示，在单细胞数据分析中，SLC2A1与B细胞的相关性最高，我们验证了其与B细胞的相关性，以及其表达与FA相关基因、肿瘤侵袭性、干性和药物敏感性的相关性。我们的研究根据 FA 相关基因和肿瘤干性相关特异基因构建了风险评分。除了能准确预测 LC 患者的预后外，该风险评分还可作为免疫疗法反应的一种创新而可行的预测指标。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.