Immunosurveillance of breast glands with oncogenic germline mutations

Project Summary/Abstract The overarching goal of the proposed research is to realize the immune system's potential for breast cancer prevention in BRCA mutation carriers. Immunotherapeutic agents have proven effective in treating metastatic cancers by reinvigorating the antitumor immune responses that develop during cancer progression and

metastasis. In contrast, our research focuses on cancer immunoprevention and aims to identify the immune pathways that can prevent breast cancer formation in normal breast glands and block pre-cancerous lesions from advancing to invasive disease in BRCA mutation carriers. This approach raises a unique opportunity to

discover novel immune mechanisms that can be leveraged for breast cancer prevention and therapy in this high- risk population. With the ultimate goal of early interception that will eliminate the risk of metastatic disease, we will investigate the underlying mechanisms of immune cell activation that we have discovered in the BRCA

mutant breast glands. We will (1) determine the breast gland-derived immune factors that induce the immune response in BRCA mutant breast glands, (2) examine the characteristics of the immune cells infiltrating BRCA mutation breast glands, (3) investigate the impact of the immune cells in BRCA mutant breast glands on cancer

development, and (4) identify novel interventions that can potentiate antitumor functionality of immune cells in BRCA mutant breast glands. Importantly, we will leverage our optimized animal models to elucidate critical immune pathways regulating BRCA mutant breast glands that are difficult to discern in human tissues due to

inter-patient heterogeneity. Ultimately, the proposed research aims to establish the foundation for breast cancer immunoprevention, benefiting patients at high risk of breast cancer development and recurrence.