Prime/boost immunotherapy of HPV16-induced tumors with E7 protein delivered by Bordetella adenylate cyclase and modified vaccinia virus Ankara.
The Bordetella adenylate cyclase toxoid (CyaA) targets cells expressing the alphaMbeta2 integrin receptor CD11b/CD18 (CR3 or Mac-1) and can penetrate into cytosol of professional antigen-presenting cells, such as dendritic cells. This allows us to use CyaA for delivery of passenger antigens into the cytosolic pathway of processing and MHC class I-restricted presentation, which can promote induction of antigen-specific CD8+ cytotoxic T-lymphocyte immune responses. We show here that vaccination with a genetically detoxified CyaA336/E7 protein, carrying the full-length oncoprotein E7 of the human papilloma virus 16 inserted at position 336 of the cell-invasive AC domain of CyaA, induces an E7-specific CD8+ T-cell immune response and confers on mice protective, as well as therapeutic immunity against challenge with TC-1 tumor cells expressing the E7 oncoprotein. The therapeutic efficacy of priming with the CyaA336/E7 vaccine could further be enhanced by a heterologous booster immunization with a highly attenuated modified vaccinia virus Ankara (MVA) expressing the E7 protein fused to the lysosome-associated membrane protein (LAMP1). These results establish the potential of CyaA as a new antigen delivery tool for prime/boost immunotherapy of tumors.
Mackova
Jana
J
Department of Experimental Virology, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20, Prague 2, Czech Republic.
Stasikova
Jana
J
Kutinova
Luda
L
Masin
Jiri
J
Hainz
Petr
P
Simsova
Marcela
M
Gabriel
Pavel
P
Sebo
Peter
P
Nemeckova
Sarka
S
D037361:Adenylate Cyclase Toxin; D000818:Animals; D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D052162:Human papillomavirus 16 / Q000472:pathogenicity*; D007111:Immunity, Cellular; D007117:Immunization, Secondary; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus
D037361:Adenylate Cyclase Toxin; D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D019496:Cancer Vaccines; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16