Novel Targets for Protection of T Cells From Tumor-Induced Dysfunction

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DESCRIPTION (provided by applicant): Ovarian cancer is a leading cause of cancer mortality. Chemotherapy is effective in reducing tumor burden in a majority of patients, however, only approximately 20% of advanced disease patients will ultimately survive tumor-free, and further treatment options are needed. Continuing advances in immunology make immunotherapy an active area for current and future research. However, the design of immunotherapeutic strategies for ovarian cancer requires an understanding of the immune microenvironment of the peritoneal cavity, the site where the most devastating effects occur. Evidence is accumulating to suggest that apoptotic death and enhanced susceptibility to apoptosis are involved in the dysfunction of T lymphocytes at the tumor microenvironment. Future success of immunotherapeutic approaches for cancer patients are dependent on the protection of T cells at the tumor site and the enhancement of their efficiency. Mcl-1, a prosurvival Bcl-2 family member has recently been demonstrated to be required for the survival of mature T lymphocytes. Our preliminary results suggest that Mcl-1 has a key regulatory role in the protection of T lymphocytes from tumor-induced apoptosis that is mediated through Bim and p53. Among the pro-survival Bcl-2 family members, Mcl-1 is the major protein to undergo significant upregulated expression in response to T-cell homeostasis cytokines, IL-2, IL-7, IL-12 and IL-15. The current application will attempt to elucidate the role and functional mechanisms of Mcl-1 in the protection of OvCA-associated lymphocytes from apoptotic death at the tumor microenvironment. The underlying scientific approach combines a basic molecular analysis of the nature of cross-regulation between Mcl-1 and Bim or p53 with a translational component that utilizes these molecules as targets for the improvement of current immunotherapeutic protocols for OvCA.