Significance: Combating major diseases, such as cancer, is an important objective in the area of Life Sciences in the 6th Framework Programme. The challenging goal of vaccination in cancer-bearing patients is to induce long-lasting antigen-specific immunit y to protect the host against tumor establishment. Although in several cases tumor rejection in mice as well as in humans has been reported, the results of current tumor immunotherapy protocols are still disappointing. Background: We propose to study epito pe spreading (ES), a process whereby epitopes distinct from an inducing epitope (e.g. a vaccine) become targets of an evolving immune response. Only recently, ES was found to play a role in anti-tumor immune responses and in tumor regression following anti -tumor vaccinations. It is thus conceivable that ES can be exploited to make anti-tumor vaccines more efficient. However, the cellular and molecular mechanisms of ES are largely unknown.Dendritic cells (DC), pulsed with tumor peptides, have been used as an ti-tumor vaccines. DC induce some immune responses by cross-presentation, which seems to depend on the fusion of phagosomes with the endoplasmic reticulum and on the association of immunoproteasomes with phagosomes.Methods: We will establish a mouse model for ES following anti-tumor vaccinations by peptide-pulsed DC. We will use this model to study (a) the role and mechanisms of cross-presentation in ES, (b) ES in wild-type versus immunoproteasome-KO mice and (c) specific requirements for the processing and the nature of the tumor antigen. Our in vivo experiments will be complemented by in vitro studies to assess the cell biology of ES by microscopic techniques.Prediction: Our proposed experiments will elucidate cellular and molecular mechanisms of ES and th us increase our understanding of vaccination-induced anti-tumor immune responses. Our results are expected to have high relevance for clinical trials of anti-tumor vaccinations.
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