Upregulation of Class I MHC on Neuroblastoma Cells By NK Cell Exposure for Enhanced CTL Reactivity

Neuroblastoma is the most common solid tumor in pediatric patients, with a clear unmet need as survival rates are <20% for stage IV disease. As adjuvant immunotherapy is considered to have additional anti-tumor activity we aim to increase cytotoxic T lymphocyte (CTL)-mediated immune surveillance in neuroblastoma patients by administration of a dendritic cell-based vaccine. Neuroblastoma has developed mechanisms to circumvent CTL recognition; therefore it is our aim to find clinical strategies to make neuroblastoma susceptible for CTL killing. PRAME is highly expressed in stage IV primary neuroblastoma and PRAME-derived antigenic peptide can be presented as peptide/MHC I complexes to reactive T cells. Low MHC I expression levels on neuroblastoma cells enable them to escape CTL recognition, but MHC I levels can be increased by interferon-gamma (IFNg). Because of the clinical toxic effects of IFNg administration, we attempted to deliver IFNg to neuroblastoma via alternative routes. We added natural killer (NK) cells which recognize target cells by their lack of MHC I and found that NK cell recognition of neuroblastoma cells upregulated class I MHC surface expression. This effect was contact-dependent, however could thereafter be transferred to “naïve” neuroblastoma cells through replacement of culture supernatant. Interestingly, IFNg was not detected in the supernatants, suggesting a different factor that triggers the MHC I upregulation in neuroblastoma. Importantly, PRAME-specific T cells were specifically activated by neuroblastoma cells after exposure to NK cells. In conclusion; we showed that NK cells can regulate MHC I levels on neuroblastoma cells which transforms them into CTL targets.