An important advance in tumor immunology is the enhancement of immunogenicity of a large spectrum of tumors of co-stimulatory molecules, particularly members of the B7 family. An important and unanswered question is whether these co-stimulatory molecules simply enhance the immune response to tumor-specific antigens, or whether they serve to break immune tolerance to self antigens. In order to address this issue, the investigator has taken advantage of the B7 enhanced anti-tumor CTL response and has developed a tumor model in which a potent anti-tumor CTL response can be detected in the freshly isolated tumor infiltrating lymphocytes. The investigator has demonstrated a major antigen in the B7-transfected plasmocytoma that induces CTL in vivo is the un-mutated tumor antigen P1A, and that the P1A gene is expressed in low levels in some normal tissues. These results raise some questions regarding the relationship between tumor immunity and autoimmunity. The investigator proposes to use the P1A model system to study the immune response and tolerance to un-mutated tumor antigens. Specifically, he will address the following questions: 1) he will investigate the sites and cellular mechanisms of anti-P1A CTL responses in vivo. 2) the investigator will produce transgenic mice expressing the P1A antigen in the thymus and the TCR specific for the P1A antigen in order to study the tolerance to this antigen, and he will also use these mice to visualize the T-cell response and tolerance within the tumors. 3) The PI will take two approaches to study the impact of self tolerance on T-cell responses to tumor antigen: By comparing the CTL response to P1A and to a viral antigen when both are expressed on the same tumor, and by comparing anti-P1A CTL responses in mice with and without targeted mutations in P1A. This project will establish the effect of immune tolerance on the conditions required for induction and effector function of CTL responses against un-mutated tumor antigens. The results will have important implications for the feasibility of using these tumor antigens as targets for tumor vaccines or immune therapy, the studies may also suggest new approaches for enhancing the effectiveness of tumor immunotherapy.
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