Mechanisms of tumor escape from immune destruction include evasive strategies to avoid immune recognition, as well as active modulation and suppression of immune cell function. The applicant's recent studies suggest that ovarian carcinoma (OvCA) cells are capable of activating an intrinsic mechanism of programmed cell-death in interacting T lymphocytes in situ and in vitro. The overall goal of the study is to delineate protective mechanisms that may have potential therapeutic use against inappropriate death of T lymphocytes at the tumor site. Based on the applicant's preliminary studies, she hypothesizes that death receptors expressed on tumor-associated lymphocytes (TAL) are activated to initiate an apoptotic cell death of the lymphocytes interacting with ovarian cancer cells. She further hypothesizes that the observed apoptotic cell death can be prevented by treatment with IL-2 or IL-12 cytokines, which upregulate activity of endogenous protective mechanisms against apoptosis of lymphocytes. To test this hypothesis, the following specific aims are proposed: (1) to investigate the role of death receptors on T cells in ovarian cancer-induced apoptosis of lymphocytes; (2) to identify the intracellular mechanisms of cell death activated in T lymphocytes interacting with ovarian cancer cells; (3) to identify endogenous and cytokine-induced anti-apoptotic mechanisms which can protect lymphocytes from ovarian cancer-induced apoptosis; (4) to investigate mechanisms of lymphocyte survival activated by intraperitoneal IL-2 or IL-12 therapy of patients with ovarian cancer, as a part of concurrent phase I/II clinical trials. These studies are expected to provide insights into the role played by death receptors on lymphocytes in immunosuppression mechanisms operated in OvCA. To develop an effective cancer therapy, it is important to elucidate what determines the susceptibility of lymphocytes to tumor-mediated cell death and what mechanisms are involved in their protection. An understanding of these mechanisms is essential for developing effective therapy regimens that would render infiltrating lymphocytes resistant to tumor-induced apoptosis and prevent or reverse the immune-hyporespsonsiveness seen in patients with OvCA.
