It has now been successfully shown in a number of animal and human tumors that a specific immune response can be generated against the tumor. This foreshadows an era of immune manipulation of tumor growth and eventual recruitment of the immune system in the process of tumor destruction. The success of immunotherapy depends on further understanding of the multitude of reasons why the observed anti-tumor response is seldom effective. At the root of that understanding is the need to know the target antigen on the tumor cell. Patients with pancreatic and breast adenocarcinomas mount a specific T cell response to their tumors. CD8+ as well as CD4+ T cells can be isolated from tumor draining lymph nodes, both populations specifically recognizing epithelial mucin as the target antigen. This antigen coats the tumor cells and is also present on normal ductal epithelial cells but not recognized by the T cells until malignant transformation unmasks specific T cell epitopes. The epitopes recognized by the two T cell populations reside on a 20aa tandemly repeated peptide which comprises the mucin polypeptide core. The tandem repeat structure endows this antigen with antigenic multivalency, potentially useful in immunotherapy, which gives it the ability under certain circumstances to activate T cells directly. The ability of this antigen to stimulate both helper and cytotoxic T cells fulfills a critical requirement for establishment of an efficient immune response. Yet, the patient succumbs to the tumor. Potential reasons may be insufficient numbers of tumor-specific CTL and anergy in the helper T cell compartment. In this application we propose: I. To investigate MHC-restricted and MHC-unrestricted activation of CTL by mucin antigen in order to validate methods for in vitro and in vivo generation of large numbers of CD8+, tumor specific CTL. II. To investigate routes of antigen presentation which can lead to generation of large numbers of functional CD4+, tumor specific T helper cells. III. To investigate the state of anergy of the CD4+ T cells and ways in which this anergy may be broken, or the cells otherwise altered to provide functional help. The long term goals of the project are to fully understand the anti-tumor mucin response and its potential for immunotherapy.
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