Exploring the impact of neutrophils on lung adenocarcinoma using Mendelian randomization and transcriptomic study

Tumor immune microenvironment plays a crucial role in determining the prognosis of lung adenocarcinoma (LUAD), with the interaction of immune cells within this microenvironment contributing to a poorer prognosis. We sought to investigate the causal relationship and underlying biological mechanisms between immune cell characteristics and LUAD to offer new insights for enhancing treatment strategies. We evaluated the association between immune cell characteristics and LUAD using Mendelian randomization (MR) analysis based on genome-wide association studies summary statistics. Sensitivity analysis was performed to verify the robustness of MR results. Immune cell infiltration analysis and machine learning on bulk RNA-sequencing data were conducted to further identify immune cells associated with LUAD. Prognostic genes of LUAD were identified using single-cell RNA-sequencing data and high dimensional weighted gene co-expression network analysis. MR analysis identified three immune cell characteristics associated with LUAD, including CCR2 on granulocyte, CD25 on CD45RA + CD4 not Treg, and plasmacytoid dendritic cell, and sensitivity analysis confirmed the robustness of the associations. Machine learning identified neutrophils, hematopoietic stem cells, B cells, and myeloid progenitor cells as key immune cell characteristics related to LUAD. Neutrophil was identified as the target cell of LUAD based on the MR analysis and machine learning. Subcequently, single-cell RNA-sequencing mapped the immune microenvironment of LUAD and identified down-regulated neutrophil. In addition, robust neutrophil-macrophage communication in LUAD was revealed using the CellChat package. Finally, nine neutrophil-related prognostic genes of LUAD were identified, three of which potentially regulated neutrophil-macrophage communication. This study showed a significant correlation between neutrophil and LUAD, particularly highlighting the neutrophil-macrophage communication. This finding may enhance our comprehension of LUAD immune microenvironment and hopefully promote the discovery of new immunotherapeutic targets for LUAD and the development of related drugs.