Induced pluripotency as a potential path towards iNKT cell-mediated cancer immunotherapy.

Invariant natural killer T (iNKT) cells are characterized by the expression of an invariant Vα14-Jα18 paired with Vβ8/7/2 in mice, and Vα24-Jα18 with Vβ11 in humans, that recognizes glycolipids, such as α-galactosylceramide (α-GalCer), presented on the MHC class I-like molecule, CD1d. iNKT cells act as innate T lymphocytes and serve as a bridge between the innate and acquired immune systems. iNKT cells augment anti-tumor responses by producing IFN-γ, which acts on NK cells to eliminate MHC-non-restricted (MHC(-)) target tumor cells, and on CD8(+) cytotoxic T lymphocytes to directly kill MHC-restricted (MHC(+)) tumor cells. Thus, when iNKT cells are activated by α-GalCer-pulsed dendritic cells, both MHC(-) and MHC(+) tumor cells can be effectively eliminated. Both of these tumor cell types are simultaneously present in cancer patients, and at present iNKT cells are only the cell type capable of eliminating them. Based on these findings, we have developed iNKT cell-targeted adjuvant immunotherapies with strong anti-tumor activity in humans. However, two-thirds of patients were ineligible for this therapy due to the limited numbers of iNKT cells in their bodies. In order to overcome the problem in cancer patients, we successfully established a method to generate iNKT cells with adjuvant activity from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). In this review, we would like to outline the clinical potential for iNKT cells derived from ESCs and iPSCs for cancer immunotherapy, and the technical hurdles that must be overcome if we achieve effective ESC/iPSC-mediated cancer therapies.