The effect of a therapeutic dendritic cell-based cancer vaccination depends on the blockage of CTLA-4 signaling.
Dendritic cells (DCs) were pulsed with the H-2K(b) binding OVA(257-264)-peptide (SIINFEKL), and used as one single-injection vaccine in combination with anti-CTLA-4 monoclonal antibody (mAb) to treat mice inoculated 3 days previously with 3x10(5) E.G7-OVA lymphoma cells. Neither DC vaccination nor CTLA-4 blockage alone prevented tumor growth in tumor challenged mice. In contrast, the combination of one vaccination and injection of anti-CTLA-4 mAb lead to rejection or retarded tumor growth in more than 60% of the mice. The OVA-transgene or the SIINFEKL-epitope was not lost in the progressing tumors of vaccinated mice, however, the highest degree of anti-SIINFEKL reactivity of host CTLs in an IFN-gamma ELISPOT assay was found only in mice showing complete tumor rejection. Vaccinated mice having rejected E.G7-OVA tumors were capable of rejecting subsequent challenges with 1x10(6) E.G7-OVA tumor cells, and later on these mice even rejected wild-type EL-4 tumor cells indicating that tumor epitope spreading takes place during the process of vaccination-induced E.G7-OVA rejection. In agreement with these observations, mice having rejected E.G7-OVA tumors showed long lasting CTL memory in spleen and bone marrow towards both the SIINFEKL-peptide and other EL-4-derived tumor rejecting epitopes.
Met
Ozcan
O
Department of Medical Anatomy, The Panum Institute, The University of Copenhagen, Blegdamsvej 3, Copenhagen 2200N, Denmark. ome@mai.ku.dk
Wang
Mingjun
M
Pedersen
Anders E
AE
Nissen
Mogens H
MH
Buus
Søren
S
Claesson
Mogens H
MH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology*; D004359:Drug Therapy, Combination; D004527:Egg Proteins / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D006183:H-2 Antigens / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D013945:Thymoma / Q000188:drug therapy* / Q000276:immunology; D019076:Transgenes / Q000502:physiology; D014611:Vaccination
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D004527:Egg Proteins; D000939:Epitopes; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; C110366:OVA-8; D010446:Peptide Fragments; D010047:Ovalbumin