Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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 (OR(IVW) =0.885; 95% CI: 0.798-0.983; P (IVW) =0.022); CD27 on IgD+ CD24+ cells in lung squamous cell carcinoma (OR(IVW) =1.054; 95% CI: 1.010-1.100; P (IVW) =0.015); CCR2 on monocyte cells in lung squamous cell carcinoma (OR(IVW) =0.941; 95% CI: 0.898-0.987; P (IVW) =0.012); CD123 on CD62L+ plasmacytoid dendritic cells (OR(IVW) =0.958; 95% CI: 0.924-0.992; P (IVW) =0.017) as well as on plasmacytoid dendritic cells (OR(IVW) =0.958; 95% CI: 0.924-0.992; P (IVW) =0.017) in lung squamous cell carcinoma. CONCLUSION: 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.