Abstract:
Breast cancer is the most common malignancy in women worldwide and remains a leading cause of câncer related mortality. While the immune system plays key role in controlling tumor progression, it is often suppressed in breast cancer. Dendritic cells (DCs), which connect innate and adaptive immunity, frequently show impaired function in this context. Extracellular vesicles (EVs) have been recognized for their role in modulating the immune microenvironment, as they can carry bioactive molecules such as proteins, lipids, and microRNAs that influence immune system. The purpose of this stydy is to explore the role of EVs in DC modulation and their impact on immune regulation and cancer progression. EVs were isolated from plasma of breast cancer patients and healthy donors using ultracentrifugation and characterized through Western blot, transmission electron microscopy and nanoparticle tracking analysis. Monocyte-derived DCs (Mo-DCs) from healthy donors were differentiated in the presence of either breast cancer exosomes (BC-EVs) or healthy donor exosomes (HD-EVs). Phenotypic and functional analyses were conducted using flow cytometry, cytokine quantification, and mixed lymphocyte reactions. miR-181b expression and its target GSK3β-interacting protein (GSKIP) were assessed by qPCR and Western blot and miR-181b inhibition was used to evaluate its role in DC modulation. Findings: BC-EV-exposed Mo-DCs exhibited maturation arrest with decreased HLA-DR, CD80, CD86, CD11c expression, and increased PD-L1. These cells impaired T cell proliferation and cytokine production. BC-EVs enriched in miR-181b-5p inhibited GSKIP expression, preventing GSK3β inactivation and mTOR activation, key processes for DC maturation. Inhibition of miR-181b restored pro-inflammatory phenotype in Mo-DCs. High miR-181b expression in patients correlated with poor prognosis, while higher GSKIP levels were linked to better outcomes. BC-EVs enriched in miR-181b induce tolerogenic DC phenotype, promoting immune evasion and cancer progression. Targeting miR-181b represents a promising strategy to restore DC functionality and improve immunotherapeutic outcomes in breast cancer. Our findings provide important insights into the physiopathology of cancer and immune evasion, which could have implications for cancer prognosis and the development of effective immunotherapy approaches for breast cancer.
