This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Overcoming Tumor Tolerance through in vivo generated dendritic cells: One of the major hurdles for effective immunotherapy treatment is the existing T cell tolerance or anergy to tumor antigens. Recently, tremendous efforts have been focused on dendritic cells (DC) based vaccine using ex vivo manipulated DCs. While these conventional DC vaccine approaches showed promising outcomes in enhancing antigen presentation and T cell activation, they failed to provide sufficient and sustained immune activation to overcome tumor tolerance, in part due to the limited number of ex vivo manipulated antigen presenting DCs reaching appropriate lymphoid compartment. Here we developed a new strategy to specifically target tumor antigen gene to in vivo derived DCs in great number to stimulate substantial and sustained immune activation. This concept has been tested using foreign antigens such as hemagglutinin, however testing this concept with tumor antigens in a tumor microenvironment has been difficult. Our preliminary data suggest that using specific vectors may control the amount and type of antigen being presented in vivo. Thus, our central hypothesis is that 'in vivo generated, tumor antigen gene modified DCs will provide sustained stimulation and induce a strong anti-tumor immunity capable of tumor elimination'. The work proposed is highly innovative and will test this hypothesis in two specific aims using a native tumor antigen HER2/neu. First, she will test the hypothesis that in vivo derived HER2/neu expressing dendritic cells can stimulate a strong immune activation to overcome tolerance, using specific vectors that allow controlled and regulated antigen expression in specific cell types. Second, with this system she will test the hypothesis that this strong activation will result in sufficient recruitment of antigen specific effector T cells to tumor sites for tumor elimination. This project not only addresses the mechanisms of tumor induced anergy, a major field of research in cancer immunology, but also explores a novel concept, i.e. the roles of antigen dose, DC activation status and persistence in vivo in overcoming tumor induced tolerance.
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