In vivo modeling of breast cancer initiation to study tumor immune evasion

Breast cancer is the most common type of cancer and the second leading cause of death in women. Although early intervention is critical to ensure a favorable outcome, many women diagnosed and treated for early breast cancer recur years later with terminal disease. Therefore, there is an urgent need to prevent breast cancer recurrence, which can be achieved through better understanding of the process of early tumorigenesis. Previous studies demonstrated that, despite their very low mutation burden, early stages of ductal carcinoma in situ (DCIS) can be infiltrated by immune cells, including T cells. In some cases, this results in effective immune surveillance, while in other cases, tumor initiating cells (TICs) manage to escape immune-mediated killing resulting in disease progression. It is well characterized that as DCIS evolve into invasive ductal carcinoma, there is a shift towards an immune suppressive microenvironment. However, it is unclear how TICs evade immune surveillance during early tumorigenesis and evolve into an immune resistant entity. To effectively study the process of immune evasion during early tumorigenesis, we developed a new model of tumor initiation by leveraging intra-ductal lentiviral delivery of gRNAs in Cas9-GFP mice to induce site-specific mutations in mammary epithelial cells that ultimately lead to tumor initiation. These tumors carry patient-relevant mutations such as inactivating mutations in tumor suppressor genes. This mouse model will facilitate future studies aimed at characterizing TICs and their surrounding niche, with the aim of shedding light on the mechanisms of immune escape during tumor initiation.