Irradiation of singly and doubly transduced murine neuroblastoma cells expressing B7-1 and producing interferon-gamma reduces their capacity to induce systemic immunity.
We have previously reported that immunization with low major histocompatibility complex (MHC) class I expressing murine neuroblastoma (neuro-2a) transduced with B7-1 fails to induce significant protection to wild-type tumor challenge. In this study we investigated whether B7-1 expressing neuro-2a cells can stimulate an effective T-cell response if they were cotransduced with the interferon-gamma (IFN-gamma) gene to upregulate MHC class I. Transfer of both the IFN-gamma and B7-1 genes into neuro-2a (N-2a/B7-1/IFN) almost completely abrogated the tumorigenic potential of this tumor and improved survival when compared with mice receiving the single transductants, N-2a/IFN and N-2a/B7-1. Rejection of N-2a/B7-1/IFN was mediated primarily by CD8+ T cells. When irradiated tumor cells were tested, IFN-gamma gene transfer into neuro-2a significantly increased immunogenicity, but transfer of the B7-1 gene did not. However, nonirradiated N-2a/B7-1, N-2a/IFN, and N-2a/B7-1/IFN cells were significantly more effective in eliciting systemic immunity against subsequent wild-type tumor challenge than their irradiated counterparts. N-2a/B7-1/IFN was more immunogenic than N-2a/B7-1 but not more than N-2a/IFN, indicating that B7-1 does not further increase immunogenicity of neuro-2a over that induced by IFN-gamma transduction. These findings should be considered when designing gene modified tumor vaccines for use in human trials.
Katsanis
E
E
Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA.
Bausero
M A
MA
Panoskaltsis-Mortari
A
A
Dancisak
B B
BB
Xu
Z
Z
Orchard
P J
PJ
Davis
C G
CG
Blazar
B R
BR
D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000528:radiation effects; D016516:CD4-CD8 Ratio; D004307:Dose-Response Relationship, Radiation; D005260:Female; D007111:Immunity, Cellular / Q000528:radiation effects; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009447:Neuroblastoma / Q000276:immunology*; D015996:Survival Rate; D014161:Transduction, Genetic / Q000528:radiation effects*; D014407:Tumor Cells, Cultured / Q000378:metabolism; D015854:Up-Regulation
D018122:B7-1 Antigen; D007371:Interferon-gamma