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Wurzenberger, Cornelia (2009): Dendritic cell vaccines in tumor immunotherapy: Immune activation strategies with ligands for the Toll-like receptors 7 and 9. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

The main function of dendritic cells (DC) is to process antigenic material and present it to other cells of the immune system. As such, they act as mediators between the innate and the adaptive arm of the immune system. Due to their substantial ability to elicit effective memory responses and to break immunological tolerance to tumors, DC-based vaccines have emerged as a promising strategy for the immunotherapy of cancer. In these vaccines, the maturation state of the DC is of crucial importance for the success of vaccination, but the most effective mode of maturation is still a matter of debate. In the first part of this work, short-term activation of DC with CpG oligonucleotides as Toll-like receptor 9 ligands was investigated as a novel strategy to achieve optimal DC maturation. The kinetics of DC maturation are a critical factor for the induction of efficient immune responses, as immature DC carry the risk of inducing tolerance whereas extensive stimulation may lead to DC unresponsiveness and exhaustion. Short activation of DC for as little as 4 hours (versus 24 to 48 hours) induced fully functional DC that rapidly secreted IL 12p70 and IFN-α, expressed high levels of costimulatory and MHC molecules and efficiently presented antigen to CD4 and CD8 T cells. Furthermore, short-term activated DC overcame immune suppression by regulatory T cells and acquired high migratory potential toward the chemokine CCL21 necessary for DC recruitment to lymph nodes. In vivo, vaccination with short-term activated DC induced a strong cytotoxic T-cell response and led to the eradication of tumors. Thus, short-term activation of DC generates fully functional DC for tumor immunotherapy. These results may guide the design of new protocols for DC generation in order to develop more efficient DC-based tumor vaccines. The second part of this study centers on a novel finding characterizing Toll-like receptor 7 activation in a subpopulation of myeloid DC: in contrast to Toll-like receptor 9 ligands, Toll-like receptor 7 agonists fail to elicit secretion of bioactive IL-12p70 in these DC. This inhibition is highly selective, because other proinflammatory cytokines are efficiently induced by Toll-like receptor 7 stimulation. As IL-12 is an important cytokine for the induction of antitumoral immune responses, the regulation of IL-12p70 production upon Toll-like receptor 7 stimulation was examined by inhibition of signal transduction, use of gene-deficient mice, and a genome-wide expression analysis by microarray. Several genes were identified that modulate IL-12 production in myeloid DC. These results add to the understanding of Toll-like receptor 7 stimulation, which is a promising alternative for the maturation of human DC.