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International Immunology, Vol. 15, No. 12, pp. 1423-1430, December 2003
© 2003 Japanese Society for Immunology

Recombinant adenylate cyclase toxin of Bordetella pertussis induces cytotoxic T lymphocyte responses against HLA*0201-restricted melanoma epitopes

Gilles Dadaglio1, Sandra Morel2, Cécile Bauche3, Zhora Moukrim1, François A. Lemonnier4, Benoît J. Van den Eynde2, Daniel Ladant3 and Claude Leclerc1

1 Unit of Biology of Immune Regulations, INSERM E352, Institut Pasteur, 75724 Paris Cedex 15, France 2 Ludwig Institute for Cancer Research and Cellular Genetics Unit of the Institute of Cellular Pathology and the University of Louvain, B-1200 Brussels, Belgium 3 Unit of Biochemistry of Macromolecular Interactions (CNRS URA 2185) and 4 Unit of Antiviral Cellular Immunology, Institut Pasteur, 75724 Paris Cedex 15, France

Correspondence to: G. Dadaglio; E-mail: gdadag{at}pasteur.fr
Transmitting editor: E. Vivier

The adenylate cyclase (CyaA) of Bordetella pertussis is able to deliver CD8+ T cell epitopes into the cytosol of CD11b+ dendritic cells (DC) following its specific interaction with the {alpha}Mß2 integrin (CD11b/CD18). This delivery results in intracellular processing and presentation by MHC class I molecules of the CD8+ T cell epitopes inserted into CyaA. Indeed, we previously showed that CyaA toxins carrying a single cytotoxic T lymphocyte (CTL) epitope can induce efficient protective and therapeutic antitumor immunity in mice. With a view to elaborating cancer immunotherapy in humans using CyaA, we constructed two recombinant CyaA carrying HLA*0201-restricted melanoma epitopes. Here we show that these recombinant CyaA induce strong anti-melanoma CTL responses in HLA*0201 transgenic mice, even after a single i.v. immunization without adjuvant. These responses are long lasting, since they were also detected 5 months after the last injection. Finally, human DC treated with the recombinant CyaA were shown to process and present efficiently the melanoma epitopes to human CTL clones. Altogether, our results demonstrate that tumoral epitopes inserted into CyaA are efficiently processed and presented in association with human MHC molecules. These observations suggest that CyaA is capable of activating antitumoral CTL in humans and highlight the potential of CyaA for use in cancer immunotherapy.

Keywords: dendritic cell, tumor immunity, vaccination


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