A central problem in cancer immunology is to devise how tumor antigens could be made to stimulate and activate immune responses. Most tumor antigens are self-antigens, and likely induce immune tolerance unless they are appropriately presented to the immune system. In almost every system tested, dendritic cells are the most potent antigen-presenting cells they can stimulate and activate helper and cytotoxic T cells even when precursor T cells are quiescent and present at low frequencies, a situation that applies to tumor-reactive lymphocytes. The goal of this project is to exploit the power of dendritic cells as antigen presenters by engineering them to present tumor antigens. Thus, the rationale for this work is based on the three following premises. (I) Dendritic cells are potent antigen-presenting cells, while tumor cells are not. (ii) Gene transfer can be used for optimal selection and presentations of antigens. (iii) Gene transfer can produce sustained antigen expression in vivo. In order to test this model, we will use a defined tumor differentiation antigen of the tyrosine family in a melanoma model and a mutant p53 oncoprotein in a sarcoma model. First, gene transfer in mouse and human dendritic cells """"""""already achieved in preliminary experiments"""""""" will be optimized by testing different types of constructs with respect to conditions of transduction, stable expression, and antigen presentation in vitro and in vivo. The immune response to dendritic cells expressing tumor antigens will then be studied in vitro and in vivo. Strategies are needed to break tolerance to tumor differentiation antigens. We have found that one approach to breaking tolerance is immunization with homologous differentiation antigen to induce immunity to the self antigen expressed by tumors. Mouse models will be used in order to measure to what extent a homologous tumor antigen, expressed in and presented by syngeneic mouse dendritic cells, can break immune tolerance and induce tumor rejection. These studies will develop preclinical rationale and strategies for using genetically modified dendritic cells for immunization to defined cancer antigens.
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