Immune-based therapies offer a promising alternative treatment to radiotherapy- or chemotherapy-resistant tumors, but enthusiasm is tempered by the fact that consistently successful treatment of patients has remained elusive. The broad, long-term objective of our research is to define immune modulators that can be used to enhance the immunological control of tumors. A comparative analysis of how the immune system successfully deals with invading pathogens, yet fails to prevent tumor outgrowth, should provide important information about activation of immune responses that can be incorporated into vaccine design. Dendritic cells that have been stimulated via CD40 become highly immunogenic and upregulate the expression of costimulatory molecules. One such molecule is CD70, a member of the TNF family of cytokines. Several lines of evidence from our laboratory suggest that CD70-mediated costimulation provides an important signal for full activation of CD8+ T cells, indicating that immune therapies that target CD27-CD70 interactions may result in increased control of tumor outgrowth. However, little is known about the regulation of CD70 expression in vivo. We hypothesize that CD70 expression is preferentially upregulated on dendritic cells, and perhaps T cells, after stimulation via CD40, and that activated CD4+ T cells prominently contribute to this process by supplying CD40-ligand. To test this hypothesis and to further the potential of targeting this costimulatory pathway for enhanced immunotherapy, we propose to 1) rigorously define the expression patterns and regulation of expression of CD70 on dendritic cells and T cells in vivo, and 2) determine the relative importance of CD70 expression on DC versus T cells for the development of T cell responses after immunization. The results obtained from these studies should provide insights into how this costimulatory molecule is regulated, and provide a framework for the intelligent design of therapeutic interventions based on its immunostimulatory properties.
