Anti-tumor effect of intratumoral administration of induced pluripotent stem cell-derived NKT cells on glioblastoma through CD155/DNAM-1 interaction.

Abstract

Background: Glioblastoma is the most malignant brain tumor with the poorest prognosis, but there have been no significant therapeutic advances in the past 20 years. Intratumoral administration of invariant natural killer T (iNKT) cells for glioblastoma has recently been reported and is promising immunotherapy. However, the low presence of iNKT cells in peripheral blood made it difficult to use iNKT cells as adoptive immunotherapy. Therefore, we used induced pluripotent stem cell-derived NKT (iPS-NKT) cells and analyzed their anti-tumor effect.

Methods: Induced pluripotent stem cell-derived NKT cells were generated by the previously reported protocol. The anti-tumor effect of iPS-NKT cells was confirmed against several glioblastoma cell lines. We also analyzed the expression of natural killer cell receptors of iPS-NKT cells and ligands of glioblastoma cell lines to know which interactions are dominant. In vivo, using an orthotopic glioblastoma mouse model, we compared the survival and tumor volume in mice iPS-NKT cells administered intratumorally with those in mice of no treatment group.

Results: We demonstrated that iPS-NKT cells have anti-tumor effects even in glioma cell lines with low CD1d expression and that CD155/DNAM-1 interactions are associated with these anti-tumor effects. In the orthotopic low CD1d-expressing glioblastoma mouse model, iPS-NKT-treated mice showed markedly prolonged survival and suppressed tumor volume.

Conclusion: We confirmed the anti-tumor effects of iPS-NKT cells on glioblastoma cells in vitro and in vivo. The anti-tumor activity was suggested to be mainly due to the interaction between CD155 and DNAM-1. Intratumoral administration of iPS-NKT cells has potential anti-tumor effects on glioblastoma in the clinic.