Recombinant adenylate cyclase toxin of Bordetella pertussis induces cytotoxic T lymphocyte responses against HLA*0201-restricted melanoma epitopes.
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(M)beta(2) 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.
Dadaglio
Gilles
G
Unit of Biology of Immune Regulations, INSERM E352, Institut Pasteur, 75724 Paris Cedex 15, France. gdadag@pasteur.fr
Morel
Sandra
S
Bauche
Cécile
C
Moukrim
Zhora
Z
Lemonnier
François A
FA
Van Den Eynde
Benoît J
BJ
Ladant
Daniel
D
Leclerc
Claude
C
D037361:Adenylate Cyclase Toxin / Q000235:genetics / Q000276:immunology*; D000536:Aluminum Hydroxide / Q000276:immunology; D000818:Animals; D020134:Catalytic Domain / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D007114:Immunization; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000378:metabolism; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000276:immunology; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology
D037361:Adenylate Cyclase Toxin; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D064532:Histocompatibility Antigen H-2D; D010455:Peptides; D011993:Recombinant Fusion Proteins; D001613:beta 2-Microglobulin; D000536:Aluminum Hydroxide; D007371:Interferon-gamma; D014442:Monophenol Monooxygenase; D017351:N-Acetylglucosaminyltransferases; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase