Triple-negative breast cancer (TNBC) represents 15-20% of newly diagnosed cases of breast cancer, and is a particularly aggressive form of this disease. Due to a lack of known molecular targets, there are currently no effective targeted therapies available for patients with chemoresistant TNBC. Infiltration of the tumor by cytotoxic T-cells, which can target and kill tumor cells when functional, is correlated with improved prognosis in TNBC patients. The preliminary data presented here suggest that TNBC cells secrete kynurenine, a tryptophan catabolite with known T-cell-suppressive actions, during the part of metastasis that requires cancer cells to survive in the absence of attachment to a basement membrane (survival in forced-suspension culture). Using T-cells derived from the peripheral blood of healthy volunteer donors, these data show that purified kynurenine decreases the activation and viability of both CD4+ (helper) and CD8+ (cytotoxic) T-cells, and may increase the differentiation of T-regulatory cells, an immune cell that can suppress the function of cytotoxic T-cells. Furthermore, these preliminary data suggest that conditioned media from TNBC cells that are surviving in forced-suspension culture is suppressive of CD8+ T-cell activation, viability, and function. The preliminary data demonstrate that upregulation of the tryptophan catabolizing enzyme TDO2 is the mechanism by which TNBC cells increase their secretion of kynurenine. Using publicly available gene expression data sets, the preliminary data show that TDO2 expression is increased in breast tumors compared to normal breast tissue, and high TDO2 expression in the primary tumor is correlated with poorer patient outcomes in invasive breast cancer. Based on these data, it is hypothesized here that TDO2 activity in TNBC cells is a critical mechanism by which TNBC cells suppress the function of T-cell-mediated antitumor immunity, and that TDO2 inhibition will increase cytotoxic T-cell function and thereby decrease tumor burden in preclinical models of this aggressive disease.
In Specific Aim 1, TNBC cell lines and T-cells derived from the blood of healthy volunteer donors will be used to test whether TDO2 is required for the ability of TNBC cells to suppress antitumor T-cell functions in vitro.
In Specific Aim 2, an immunocompetent mouse model of triple-negative mammary carcinoma will be used to test whether inhibiting TDO2 decreases tumor burden, metastasis, and antitumor T-cell function in vivo. Completion of these proposed studies will determine whether TDO2 is a mechanism by which TNBC evades antitumor T-cells, and will enhance the field?s understanding of tumor immunology in breast cancer. Together, the findings from these studies will help guide development of a novel targeted therapy for treatment of this aggressive breast cancer subtype for which therapeutic options are currently limited to chemotherapy.
Triple-negative breast cancer is an aggressive disease with limited treatment options. The preliminary data shown in this proposal suggest that increased activity of the enzyme TDO2 may be a mechanism by which triple-negative breast cancer can evade the anticancer functions of the immune system. The proposed research will determine whether inhibiting TDO2 will improve the ability of the immune system to target and kill triple-negative breast cancer and decrease mortality from metastatic disease.
