Despite decades of research, breast cancer still represents second most deadly malignancy for women in the United States. Furthermore, current therapeutic options can cause disfigurement and malaise, potentially reducing quality of life. Therapies that lead to durable remission with minimal side effects are urgently needed. We propose that an integrated approach to cancer research that considers both tumor heterogeneity and associated cells in the tumor microenvironment may reveal novel therapeutic approaches. A population of cancer cells, termed cancer stem cells, has been proposed to be resistant to therapies and lead to relapse. Very little work has examined the sensitivity of breast cancer stem cells to different methods of immune-mediated killing or their ability to suppress local immune responses. We first intend to ensure that the breast cancer stem cell population we plan to study is likely to be the chemoresistant population of cells in patients with breast cancer. We will then measure the sensitivity of these cells to different mechanisms of immune-mediated killing along with their ability to protect neighboring cells from attack by immune cells. We will identify how these breast cancer stem cells interact with the immune system in order to identify potential weaknesses that can be targeted clinically to sensitize breast cancer stem cells and their neighboring cancer cells to immunotherapy approaches.