A Novel Mouse Model for Evaluation and Prediction of HLA-A2-restricted CEA Cancer Vaccine Responses

Abstract

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.