A novel mouse model for evaluation and prediction of HLA-A2-restricted CEA cancer vaccine responses.
Human leukocyte antigen (HLA)-A2.1 transgenic mice (HHD) represent a valuable model to study and predict the immunogenicity of vaccines against pathogens. However, HHD mice are unsuitable for in vivo studies of cancer vaccines against human tumor-associated antigens because they lack T-cell tolerance that is key to define the potency of the treatment. In this study, we developed HHD/carcinoembryonic antigen P(CEA) hybrid mice by breeding transgenic mice homozygous for CEA with HHD. These mice express human CEA, present epitopes solely through HLA-A2.1 molecules and constitute a unique in vivo animal model to study HLA-A2.1-restricted immune response of a human CEA-based vaccine. Owing to the immune tolerance, HHD/CEA mice show a limited immune response and expansion of a different and restricted T-cell receptor repertoire after antigen-specific stimulation. Our data show that genetic vectors expressing CEA and peptide-based vaccines are able to efficiently break immune tolerance against CEA and to elicit strong immune response against HLA-A2.1-restricted CEA epitopes. Most importantly, efficient lysis of human CEA+/HLA-A2.1+ tumor cells was observed and significant protection against HHD/CEA tumor cells was achieved in HHD/CEA-vaccinated mice. Hence, HHD/CEA provides a relevant model for the evaluation of the potential efficacy of human CEA-based vaccines.
Conforti
Antonella
A
Department of Oncology, I.R.B.M. P. Angeletti, Pomezia, Italy.
Peruzzi
Daniela
D
Giannetti
Patrizia
P
Biondo
Antonella
A
Ciliberto
Gennaro
G
La Monica
Nicola
N
Aurisicchio
Luigi
L
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D005243:Feces / Q000737:chemistry; D005260:Female; D005434:Flow Cytometry; D041981:Gastrointestinal Tract / Q000378:metabolism; D006183:H-2 Antigens / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D014611:Vaccination / Q000379:methods
D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D000939:Epitopes; D006183:H-2 Antigens; D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell