Project 467187

Breast cancer is the most frequently diagnosed cancer in women, and although the 5-year overall survival rate is over 85%, the development of therapy resistance and progression into a metastatic disease commonly occur. To this end, immune therapies are becoming increasingly popular as they have the potential to be more effective and longer lasting than current treatment options such as chemotherapy, radiation and hormone therapy. The immune system's ability to target a tumor can become weakened and mechanisms that allow for cancer progression can be acquired. During immunotherapy, immune cells are manipulated in an effort to strengthen or restore the immune system's ability to detect and control tumor growth. In Adoptive Cell Transfer (ACT), tumor-infiltrating lymphocytes (TIL) are collected from the tumor, expanded outside of the body and reintroduced into the patient as a therapeutic agent. Breast cancer patients, however, fail to respond to T cell-based therapies because TILs become exhausted from antigenic overstimulation in the tumor environment and are eventually incapable of controlling tumor growth. I hypothesize that the breast tumor-adjacent tissue (TAT) may represent an alternative source of non-exhausted tumor-reactive T cells that can be harnessed for ACT therapy in patients. Toward this hypothesis, I have two major aims. In the first aim, I will identify and characterize the different T cell subtypes present in breast tumors and the matching TAT samples using a single-cell RNA sequencing platform. In the second aim, I will perform functional assays to assess which of the differentially present T cell subsets in the TAT samples are the most effective in breast cancer cell elimination by placing autologous T cells with breast cancer cells in 3D co-cultures.