先前的研究强调了免疫细胞在肺癌发展中的关键作用。然而，免疫表型与肺癌之间的直接联系仍未得到充分探索。我们应用了两个样本孟德尔随机化 (MR) 分析，使用遗传变异作为工具来确定暴露对结果的因果影响。与传统的随机对照试验 (RCT) 不同，该方法利用受孕时随机遗传的遗传变异，从而减少混杂因素并防止反向因果关系。我们的分析涉及三项全基因组关联研究，以使用遗传工具变量 (IV) 评估 731 个免疫细胞特征对肺癌的因果影响。我们最初使用标准逆方差加权 (IVW) 方法，并使用三种补充 MR 技术（MR-Egger、加权中位数和 MR-PRESSO）进一步验证我们的研究结果，以确保稳健性。我们还进行了 MR-Egger 截距和 Cochran's Q 检验来评估异质性和多效性。此外，还使用 ​​R 软件进行所有统计计算，进行反向 MR 分析，以探索肺癌亚型和已识别的免疫表型之间的潜在因果关系。我们的 MR 分析确定了 106 个与肺癌显着相关的免疫特征。值得注意的是，我们在所有敏感性测试中发现了五个提示性关联（P<0.05）：小细胞肺癌中 IgD-CD24-细胞上的 CD25（ORIVW = 0.885；95% CI：0.798-0.983；P IVW = 0.022）；肺鳞状细胞癌中 IgD CD24 细胞上的 CD27（ORIVW =1.054；95% CI：1.010-1.100；P IVW =0.015）；肺鳞状细胞癌中单核细胞上的 CCR2（ORIVW =0.941；95% CI：0.898-0.987；P IVW =0.012）； CD62L 浆细胞样树突状细胞 (ORIVW = 0.958; 95% CI: 0.924-0.992; P IVW = 0.017) 以及浆细胞样树突状细胞 (ORIVW = 0.958; 95% CI: 0.924-0.992; P IVW = 0.017) 上的 CD123肺鳞状细胞癌。这项研究在免疫细胞和肺癌之间建立了显着的基因组联系，为未来针对肺癌治疗的临床研究提供了坚实的基础。版权所有 © 2024 Xu，Fang，Shen，Zhou，Zhang，Ke，Chen and鲁。

Previous studies have highlighted the crucial role of immune cells in lung cancer development; however, the direct link between immunophenotypes and lung cancer remains underexplored.We applied two-sample Mendelian randomization (MR) analysis, using genetic variants as instruments to determine the causal influence of exposures on outcomes. This method, unlike traditional randomized controlled trials (RCTs), leverages genetic variants inherited randomly at conception, thus reducing confounding and preventing reverse causation. Our analysis involved three genome-wide association studies to assess the causal impact of 731 immune cell signatures on lung cancer using genetic instrumental variables (IVs). We initially used the standard inverse variance weighted (IVW) method and further validated our findings with three supplementary MR techniques (MR-Egger, weighted median, and MR-PRESSO) to ensure robustness. We also conducted MR-Egger intercept and Cochran's Q tests to assess heterogeneity and pleiotropy. Additionally, reverse MR analysis was performed to explore potential causality between lung cancer subtypes and identified immunophenotypes, using R software for all statistical calculations.Our MR analysis identified 106 immune signatures significantly associated with lung cancer. Notably, we found five suggestive associations across all sensitivity tests (P<0.05): CD25 on IgD- CD24- cells in small cell lung carcinoma (ORIVW =0.885; 95% CI: 0.798-0.983; P IVW =0.022); CD27 on IgD+ CD24+ cells in lung squamous cell carcinoma (ORIVW =1.054; 95% CI: 1.010-1.100; P IVW =0.015); CCR2 on monocyte cells in lung squamous cell carcinoma (ORIVW =0.941; 95% CI: 0.898-0.987; P IVW =0.012); CD123 on CD62L+ plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) as well as on plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) in lung squamous cell carcinoma.This study establishes a significant genomic link between immune cells and lung cancer, providing a robust basis for future clinical research aimed at lung cancer management.Copyright © 2024 Xu, Fang, Shen, Zhou, Zhang, Ke, Chen and Lu.