Despite considerable evidence supporting the existence of host immunity to tumors, attempts to elicit anti-tumor immune responses in human shave had only limited success. A critical challenge in tumor immunology is antigen delivery. Dendritic cells (DC's) are potent antigen presenting cells, capable of initiating antigen-specific T cell-dependent immune responses. The goal of this proposal is to elucidate key factors determining the in vivo immunogenicity of DC-based immunizations and to manipulate these factors to develop innovative strategies for using DC's to induce T-cell mediated tumor immunity. To accomplish this we will pursue 2 specific aims.
In SPECIFIC AIM 1, we will perform experiments to determine the molecular basis for ex vivo antigen-loading of dendritic cells. They hypothesis underlying this aim is that the capacity of DC's to generate and/or present peptide epitopes from various forms of administered antigen will be a critical factor in determining immunogenicity. Our goal is to determine parameters of DC antigen loading which will result in optimal T-cell mediated tumor immunity. To achieve this goal we will study the capacity of DC's to generate and present relevant peptide epitopes from various forms of administered antigen. Studies in SPECIFIC AIM 2 are designed to define and manipulate factors critical to in vivo immunogenicity of antigen-loaded DC's. They hypothesis underlying this aim is that factors in addition to antigen loading will affect antigen presentation, DC trafficking and localization, and ultimately the immunogenicity of antigen-loading DC's in the host. The goal is to elucidate key factors influencing the in vivo immunogenicity of antigen-loaded dendritic cells and to manipulate these factors to induce tumor immunity in vivo. Parameters which will be investigated include: method of antigen load, lineage and """"""""maturity"""""""" of DC's, and the dose, sequence and route of administration. Insights gained from these studies should be directly applicable to the design of innovative strategies for DC-based anti-tumor immunization.
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