Causality between immune cells and HER2-breast cancer: A 2‑sample Mendelian randomization study

This study represents the first investigation employing 2-sample Mendelian randomization (MR), multi-marker analysis of genomic annotation (MAGMA), Metascape, and the Kaplan-Meier (K-M) plotter database to elucidate the causal relationship between immune cells (ICs) and human epidermal growth factor receptor 2 negative breast cancer (HER2-BC). The findings provide genetic evidence supporting the association between ICs and HER2-BC risk. The 2-sample data for the Mendelian randomization study were sourced from public databases. In this study, ICs were selected as the exposure factor, and HER2-BC was taken as the outcome factor. MR analysis was conducted on the causal relationship between ICs and HER2-BC by using various regression models. Gene-based analysis was carried out through MAGMA, and the gene functions and pathway enrichments of the genes identified through Metascape analysis were explored. Finally, based on the K-M plotter database, the survival status of some ICs was analyzed. Among the 731 ICs, a total of 33 ICs were found to have a protective effect on HER2-BC, while 17 ICs had an adverse effect. After false discovery rate-bonferroni (PFDR < .05) correction, we detected 2 risk immunophenotypes of HER2-BC: human leukocyte antigen (HLA) DR on plasmacytoid DC, activated and secreting Treg %CD4+. A total of 38 genes were identified by MAGMA analysis. Metascape analysis revealed that the identified pleiotropic genes participated in negative regulation of cell migration, VEGFA-VEGFR2 signaling pathways. The survival analysis based on K-M plotter found that when CD4, HLA-DRB1, HLA-DRA, and ESR1 are highly expressed, the upper quartile survival rate of OS, RFS, and distant metastasis free survival is longer. This study showed that the immune response affects the progress of HER2-BC in a complex mode. These findings greatly improve our understanding of the interaction between immune response and HER2-BC risk, and also help to design therapeutic strategies for HER2-BC from the perspective of immunology.