Antigen-specific regression of established tumors induced by active immunization with irradiated IL-12- but not B7-1-transfected tumor cells.
Transfection of modestly immunogenic tumors to express B7 family co-stimulator molecules results in their rejection by syngeneic mice, suggesting a possible clinical application in cancer patients. Immunization of naive mice with irradiated B7-1-transfected P1.HTR cells is sufficient to induce specific cytolytic T lymphocytes (CTL) and to protect against tumor challenge. However, patients to be treated will have an existing tumor burden; thus, preclinical models should examine therapeutic efficacy in an established tumor setting. Contrary to expectations, immunization of mice with irradiated B7-1-transfected P1.HTR cells had no impact on the growth of pre-established control-transfected tumors. Mice bearing control-transfected P1.HTR tumors successfully rejected living B7-1 transfectants on the contralateral flank, demonstrating the ability of tumor-bearing mice to respond to B7 co-stimulation. Inasmuch as IL-12 is another important factor for CTL maturation, P1.HTR transfectants expressing B7-1 and/or IL-12 were then constructed. Remarkably, regression of pre-established tumors was achieved following immunization with irradiated IL-12 transfectants, even without co-expression of B7-1. Rejection required a shared antigen with the tumor used for immunization, could not be reproduced with rIL-12 alone, depended on host T lymphocytes and correlated with a high IFN-gamma-producing T cell phenotype. In addition, IL-12-facilitated tumor rejection required co-operation with a CTLA-4 ligand provided by the host, and correlated with up-regulation of B7-1 and B7-2 on host antigen-presenting cells. Thus, active immunization in the established tumor setting is benefitted greatly by the provision of IL-12, which may recruit participation of sufficient B7 co-stimulation from the host that it need not be provided exogenously.
Fallarino
F
F
Department of Medicine, University of Chicago Medical Center, IL 60637, USA.
Ashikari
A
A
Boon
T
T
Gajewski
T F
TF
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D000951:Antigens, Neoplasm / Q000276:immunology*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics* / Q000528:radiation effects; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000276:immunology*; D002455:Cell Division / Q000276:immunology / Q000528:radiation effects; D004357:Drug Synergism; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D018796:Immunoconjugates; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics* / Q000528:radiation effects; D007939:Leukemia L1210; D008024:Ligands; D012515:Mast-Cell Sarcoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014162:Transfection / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D000939:Epitopes; D018796:Immunoconjugates; D008024:Ligands; D018664:Interleukin-12; D000069594:Abatacept