Heat shock proteins (HSP) are gaining increasing attention in immunology because of their two critical functions: (1) their ability to chaperone and present antigenic peptides to specific T cells; (2) their emerging roles in activating antigen presenting cells. It has been shown that the constitutive secretion of an endogenous HSP gp96 leads to potent immunogenicity of tumors. Since surface expression and secretion of gp96 have been observed in a variety of cell types, this application hypothesizes that the surface expression and secretion of gp96-peptide complexes precedes cell death as the first mode of antigen release into the tumor microenvironment, which is therefore important in the priming of tumor- specific T cells. The specific objectives are: (1) To determine if tumor cells with gp96 targeted extracellularly are more immunogenic in solid tumor model; (2) To study the differences of mechanisms of immunity elicited by wild type tumor cells, with surface-expressing tumor cells and tumors that secrete gp96 constitutively; (3) To perform a pre-clinical study of immunotherapy of spontaneous breast cancer in a Her-2/neu transgenic mouse model with breast cancer cells engineered to express gp96 extracellularly; (4) To initiate a pilot phase I study for the treatment of patients with Her-2/neu expressing cancer using tumor cells that secrete gp96 constitutively. The applicant's interests are in the early events in priming tumor-specific T cells. Ultimately, he hopes to develop immunologically based cancer treatment strategies, thus combining his training in both immunology and medical oncology. After 5 year clinical training, he now returns to the field he started, and to his Ph.D. mentor, Pramod K. Srivastava, who pioneered the field of HSP in immunity, and is committed to the full independence of the applicant.
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