The overall goal of our studies is learn how tumor-specific CD8+ effector T cell function is regulated, and to enhance the ability of these T cells to eradicate tumors. The underlying hypothesis of this grant proposal is that normal mechanisms that regulate T cell responses and limit autoimmunity also impair effective CD8+ T cell mediated anti-tumor responses. Therefore, tumor-specific T cells with phenotypes typical of effectors in autoimmune disease may be more potent mediators of tumor-immunity. We will test if modification of regulatory pathways can enhance their ability to mediate anti-tumor responses. We shall explore the following: 1) By engineering TGF-beta-resistant tumor-specific cytolytic T lymphocytes (CTL) we will be able to assess whether these cells are more potent anti-tumor effectors than their TGF-beta-sensitive counterparts; 2) producing tumor-specific CTL with a dysregulated imunoinhibitory pathway because of a lack of CTLA-4, will allow us to determine if the anti-tumor cytolitic function of these cells increases compared to wild-type CTL effectors and 3) generating tumor-specific CTL with enhanced migratory phenotypes by altering adhesion molecule or chemokine receptor expression, will enable us to investigate if these cells are better able to mediate tumor rejection than unmodified CD8 effectors.
