TIMELY IMMUNIZATION SUBVERTS THE DEVELOPMENT OF PERIPHERAL NONRESPONSIVENESS AND SUPPRESSES TUMOR-DEVELOPMENT IN SIMIAN-VIRUS-40 TUMOR ANTIGEN-TRANSGENIC MICE

Tolerance to tumor cell expressed molecules and selection of cells tha t evade immune surveillance during tumor progression create effective barriers to immunotherapy. We investigated the cytotoxic T-lymphocyte response to simian virus 40 (SV40) tumor (T/t) antigen in two lineages of transgenic mice bearing the same rat insulin promoter-SV40 T/t ant igen (RIP Tag) hybrid gene. RIP1-Tag2 mice, which express Tag as embry os, are tolerant to Tag, whereas RIP1-Tag4 mice, which express the tra nsgene in pancreatic islet beta cells several weeks after birth and de velop insulinomas, can be immunized to generate active Tag-specific cy totoxic T lymphocytes as determined by in vitro assays. Indeed, RIP1-T ag4 mice immunized with Tag by SV40 infection prior to the time of end ogenous transgene expression also mount an effective in vivo cellular immune response to the Tag-expressing pancreatic beta cells, and Tag-i nduced tumor growth is significantly delayed (up to 1 year). However, after the transgene is expressed, RTP1-Tag4 mice are unable to mount a tumor-inhibiting response upon immunization, although Tag specific cy totoxic T cells can still be demonstrated in vitro. Our data suggest t hat Tag-specific T cells are rendered unresponsive in vivo in RIP1-Tag 4 mice and that the establishment of this unresponsiveness to Tag can be prevented by SV40 immunization only before the onset of the transge ne expression. In the older, successfully immunized mouse, decreased i mmune surveillance and selection of cells with down-regulation of majo r histocompatibility complex class I expression most likely set the st age for insulinoma development.