It is a long-standing observation in tumor immunology that T cell therapy for mouse cancers is rarely effective once the cancers have established themselves for more than a week in the host. If the tumor-specific T cells are not optimally activated until the cancer has reached a large mass, as our preliminary data indicate, the effector T cells, developed during tumorigenesis, would always have to face large tumor burdens. Therefore, the key to understanding the effector function of tumor-specific CTL is to understand how T cells deal with large tumors. In the next funding period, the investigators will take advantage of the valuable tools they have developed to address three critical issues related to T cell immunity against large tumor burden. First, how does tumor burden affect the direct and cross priming of tumor-specific T cells? Second, what is the immunological basis for the inability of tumor-specific CTL to eliminate the large burden of established tumors? Third, can tumor cells induce clonal deletion of tumor-reactive T cells in the thymus? If so, can a blockade of such deletion tilt the balance between tolerance and immunity towards immunity? The proposed studies will use defined T cells and antigens to analyze T cell immune response in mice with large tumor burdens. This will not only reveal the basic principles of anti-tumor immune response, but will also allow us to rationally design T cell immunotherapy.