The long range goal of this project is to develop methodology to induce melanoma immunity by immunization with particulate antigens. The emphasis will be on the induction of cytotoxic T lymphocyte (CTL) mediated immunity, since CTL are a critical component of the immune response to tumors. Melanoma has been chosen as the tumor target, 1) since it is among the most aggressive human cancers, 2) the number of new cases is growing steadily and 3) CTL are a significant component of the immune response to melanoma. Generally CTL recognize peptides generated from endogenous proteins in the cytosol. Because proteins in the extracellular fluids generally cannot enter the cytosol and access the class I presentation pathway, immunizations with killed pathogens or component proteins do not elicit CTL immunity in most cases. Recent studies demonstrate that some phagocytic antigen presenting cells (APCs) can process and present exogenous particulate antigens with MHC class I molecules. In the APCs, antigens in phagolysosomes gain access to the cytosol, and subsequently share a final common pathway with endogenously synthesized proteins for MHC class I presentation. The applicant proposes that targeting exogenous antigen into this pathway in vivo could potentially prime CTL responses to tumors.
The specific aims are 1) to induce tumor specific CTL immunity by administration of particulate antigens in murine melanoma models and 2) to optimize particulate antigen immunization strategies.
| Deng, J S; Falo Jr, L D; Kim, B et al. (1998) Cytotoxic T cells in basal cell carcinomas of skin. Am J Dermatopathol 20:143-6 |
