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

Area of Science:

• Immunology
• Oncology
• Genetics

Background:

• Human epidermal growth factor receptor 2 negative breast cancer (HER2-BC) is an aggressive subtype with complex interactions with the immune system.
• Understanding the causal relationship between immune cells (ICs) and HER2-BC risk is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the causal relationship between various immune cells and HER2-BC risk using a multi-omics approach.
• To identify specific immune cell types and genetic pathways that influence HER2-BC development and patient survival.

Main Methods:

• Employed 2-sample Mendelian randomization (MR) to assess causality between ICs and HER2-BC.
• Utilized Multi-marker Analysis of Genomic Annotation (MAGMA) for gene-based analysis.
• Performed Metascape analysis for gene function and pathway enrichment.
• Analyzed survival data using the Kaplan-Meier (K-M) plotter database.

Main Results:

• Identified 33 ICs with a protective effect and 17 with an adverse effect on HER2-BC risk.
• Detected two risk immunophenotypes: human leukocyte antigen (HLA) DR on plasmacytoid dendritic cells (DCs) and activated, secreting regulatory T cells (Tregs) %CD4+.
• MAGMA identified 38 genes, with Metascape revealing involvement in negative regulation of cell migration and VEGFA-VEGFR2 signaling pathways.
• High expression of CD4, HLA-DRB1, HLA-DRA, and ESR1 correlated with improved overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival.

Conclusions:

• The immune response significantly influences HER2-BC progression through complex mechanisms.
• Genetic evidence supports a causal link between specific immune cells and HER2-BC risk.
• Findings enhance understanding of immune-HER2-BC interactions and inform the design of novel immunotherapeutic strategies for HER2-BC.