Therapy of murine tumors with recombinant Bordetella pertussis adenylate cyclase carrying a cytotoxic T cell epitope.
Bordetella pertussis secretes an invasive adenylate cyclase toxin, CyaA, that is able to deliver its N-terminal catalytic domain into the cytosol of eukaryotic target cells directly through the cytoplasmic membrane. We have shown previously that recombinant CyaA can be used to deliver viral CD8+ T cell epitopes to the MHC-class I presentation pathway to trigger specific CTL responses in vivo. In the present study, we show that mice immunized with a detoxified but still invasive CyaA carrying a CD8+ T cell epitope of OVA developed strong epitope-specific CTL responses, which kill tumor cells expressing this Ag. Treating mice with this recombinant molecule after the graft of melanoma cells expressing OVA induced a strong survival advantage compared with control animals. To our knowledge, this study represents the first demonstration that a nonreplicative and nontoxic vector carrying a single CTL epitope can stimulate efficient protective and therapeutic antitumor immunity.
Fayolle
C
C
Unité de Biologie des Régulations Immunitaires, Centre National de la Recherche Scientifique, Unité de Recherche Associée 1129, Institut Pasteur, Paris, France.
Ladant
D
D
Karimova
G
G
Ullmann
A
A
Leclerc
C
C
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology* / Q000302:isolation & purification; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology*; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000235:genetics / Q000276:immunology*
D037361:Adenylate Cyclase Toxin; D001426:Bacterial Proteins; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D011498:Protein Precursors; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D010047:Ovalbumin; D000262:Adenylyl Cyclases