TRANSFORMING GENES AND IMMUNOLOGICAL TUMOR REGRESSION

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Transforming genes are essential for the development of cancer, and some of these genes encode strong antigens that can elicit tumor regression by CD+ T cells. One common goal of this Project is the identification of CTL- recognized peptide epitopes on antigens with such oncological and immunological, i.e. antigens encoded by human papilloma virus (HPV) and antigens found experimentally induced murine tumors. An additional goal of this Project is to understand how these CTL epitopes can be most effectively presented to the immune system. A final goal is to understand how cancer escape immune responses to these transforming proteins. Dr. Kast will explore the use of virus-like particles (VLPs) to immunize against products of transforming genes and plans to induce murine and human CD8+ T cells to transforming proteins of HPV, a major causative agent of human cervical cancer. Using experimental tumors as models, Dr. Schreiber will determine whether the unique antigens that are the prominent rejection antigen on chemically and physically induced tumors are due to somatic mutations (and thus truly tumor-specific), whether these mutant proteins have significance in the malignant process and whether unique antigens that are lost from and those that are retained by progressor tumors differ in oncogenic efforts in immunogenicity. Dr. Argon will explore the cell-biological mechanisms that allows hat-shock proteins to bind and traffic viral or tumor-specific mutant peptides and "deliver" them to the MHC Class I molecules for presentation to CD8+ T cells. Finally, Dr. Meredith will give advice and guidance on the multiple biochemical aspects of the program and produce essential reagents. Together the three projects will define conditions and mechanism by which CD8+ T cell responses to peptides encoded by transforming genes lead to tumor destruction.