PURPOSE: Dendritic cell (DC)-based tumor vaccines have been tested extensively to treat cancer patients. However, the results of several DC-based clinical trials have been disappointing. Amelioration of such a modality for cancer treatment seems warranted, i.e. by improving DC immunogenicity and polarization. The goal of our study was to evaluate the potential for immune activation of human DCs by incubating them in vitro with the Newcastle Disease Virus (NDV), a paramyxovirus with strong immunostimulatory properties.
RESULTS: In vitro infection with NDV of human monocyte-derived DCs–generated from peripheral monocytes cultured with IL-4 and GM-CSF–induces the generation of viral M gene transcripts and RIG-I expression within DCs. Expression of both genes was increased upon co-stimulation with LPS. Surprisingly, LPS and NDV had opposite effects on induction of interferon (IFN)-alpha. Furthermore, NDV induced DC maturation (as measured by TNF-alpha production and CD80 cell surface expression) only in the presence of LPS. Most interestingly, an optimal combination of NDV and LPS caused polarization of the DCs to Th1 type cytokines with a high ratio of interleukin (IL)-12 to IL-10.
CONCLUSION: These in vitro results provide a means and protocol for maturation and activation of DCs with enhanced and sustained T helper type 1-polarizing capacity. Such pretreated DCs may significantly improve DC-based cancer immunotherapy. The data encourage the use of RNA-based viral vectors as potential novel and powerful gene transfer modality for cytoplasmic gene expression in professional antigen-presenting cells (APC) to overcome immunosuppression in cancer patients.