Vaccination with dendritic cells pulsed in vitro with tumor antigen conjugated to cholera toxin efficiently induces specific tumoricidal CD8+ cytotoxic lymphocytes dependent on cyclic AMP activation of dendritic cells.
We investigated the development of CD8+ tumor-specific cytotoxic lymphocytes (CTL) and protection against tumor growth after vaccination with bone marrow-derived dendritic cells (DC) pulsed with a model protein ovalbumin conjugated to cholera toxin (OVA-CT) in B6 mice using E.G7 tumor cells expressing OVA(257-264) peptide (SIINFEKL) as target cells in vitro and in vivo. Vaccination with OVA-CT-pulsed DC concurrently induced strong CTL in vitro activity and anti-E.G7 tumor protection in vivo in WT, NK-depleted and CD4-deficient mice as well as in IL-12-/- and IFN-gamma-/- mice but not in CD8-deficient mice. Importantly, activation of CTL by OVA-CT-pulsed DC was dependent on CT-induced activation of adenylate cyclase and increased cAMP production by DC associated with increased expression of MHC class I and co-stimulatory molecules (CD80, CD86 and CD40). These results show that vaccination with DC pulsed with antigens (Ag) conjugated to CT induces a strong CTL response and suggest that conjugation of tumor Ag to CT for DC vaccination represents a promising approach for tumor vaccination and immunotherapy.
Sun
J-B
JB
Department of Medical Microbiology and Immunology, and Göteborg University Vaccine Research Institute (GUVAX), Göteborg University, S-405 30, Göteborg, Sweden. jia-bin.sun@microbio.gu.se
Eriksson
K
K
Li
B-L
BL
Lindblad
M
M
Azem
J
J
Holmgren
J
J
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000494:pharmacology; D002772:Cholera Toxin / Q000276:immunology* / Q000494:pharmacology; D000242:Cyclic AMP / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D004527:Egg Proteins / Q000276:immunology / Q000494:pharmacology; D005434:Flow Cytometry; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive / Q000379:methods*; D000922:Immunotoxins / Q000276:immunology* / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D010446:Peptide Fragments; D013047:Specific Pathogen-Free Organisms; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D004527:Egg Proteins; D000922:Immunotoxins; C110366:OVA-8; D010446:Peptide Fragments; D007371:Interferon-gamma; D010047:Ovalbumin; D002772:Cholera Toxin; D000242:Cyclic AMP