About 10-15% of breast cancer (BC) patients have their cancers spread to the brain (brain metastasis, or BrM) at late-stage of diseases. Particularly, one third of patients with HER2 gene overexpression (HER2+) or triple-negative BCs will develop BrM. Sadly, there are currently no effective treatments for BC BrM, resulting in a median survival time of only 7.2 months and extremely poor quality of life. If we can prevent BrM development, BC patients will have significantly longer survival and better quality of life. Since BrM usually develop much later, we reason that after patients are diagnosed with HER2+ or triple-negative BC, the long latent time is an opportunity to prevent or intervene...

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About 10-15% of breast cancer (BC) patients have their cancers spread to the brain (brain metastasis, or BrM) at late-stage of diseases. Particularly, one third of patients with HER2 gene overexpression (HER2+) or triple-negative BCs will develop BrM. Sadly, there are currently no effective treatments for BC BrM, resulting in a median survival time of only 7.2 months and extremely poor quality of life. If we can prevent BrM development, BC patients will have significantly longer survival and better quality of life. Since BrM usually develop much later, we reason that after patients are diagnosed with HER2+ or triple-negative BC, the long latent time is an opportunity to prevent or intervene in BrM formation. This proposal aims to develop a new approach called immunoprevention to prevent BC BrM. Immunoprevention uses the body's own immune system to fight cancer and metastasis. But, BrM poses unique challenges because the brain has a limited immune response to cancer. To cope with the challenges, we will focus on special immune cells called dendritic cells (DCs), which play a key role in activating T-cell tumor-killing immune responses. We will modify these DCs by inhibiting a DC inhibitory molecule, called SHP1, to enhance DCs' immune-stimulating abilities and load DCs with BC-specific antigen proteins. DCs can secrete vesicles called extracellular vesicles (EVs). We will isolate EVs from activated DCs (DCEVs) that can present tumor antigens and travel inside the brain when intranasally delivered. We expect that these special DCEVs can enhance immune surveillance in the brain to prevent or intervene in the development of BrM when given before HER2 positive and triple-negative BC cells reach the brain. We will also dissect the mechanisms of the DCEVs-enhanced immune response in the brain. If successful, this research will help not only BC patients at risk of developing BrM, but also patients with other types of cancer of high BrM potential.

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