The proposed research will investigate how the immune system responds to breast cancer, and how best to manipulate the immune response to treat established tumors. Our group developed a transgenic mouse model of breast cancer, in which mice develop spontaneous mammary tumors at 6-9 months of age. Tumors are engineered to express a model antigen (ovalbumin) that can be recognized by the immune system. We then try to cure tumors by infusing immune cells (specifically "helper and killer T cells") that recognize the tumor. Using this system, we have shown that ~35% of mammary tumors can be completely eradicated by T cell infusion without the need for any other form of treatment. This is among the most striking examples of successful T cell therapy ever reported. However, ~65% of tumors somehow survive the T cell attack. In our first cycle of funding, we showed that many tumors resist T cell attack by physically blocking the entry of T cells into the centre of the tumor; such tumors are said to have an "infiltration barrier". In Aim 1, we will use modern genomic approaches to dissect tumors at a molecular level to better understand what makes tumors sensitive or resistant to T cell therapy. In Aim 2, we will alter the expression of key genes in tumors and test whether this increases or decreases their sensitivity to T cell therapy. Finally, in Aim 3 we will apply similar approaches to human breast tumors that have elicited either strong or weak T cell responses in patients. This study will advance our understanding of the immune response to breast cancer and generate new strategies to enhance immune-based treatments. In future, it may be possible to better predict which patients will respond to immunotherapy, and how best to enhance the immune response as a new form of treatment.