Creating a life-saving killer

Upon receiving the appropriate activating signal, natural killer T (NKT) cells live up to their name, releasing a torrent of molecules that trigger the protective immune response necessary to eliminate pathogens or even thwart tumor growth.

These cells represent a promising clinical tool, as demonstrated in a recent clinical trial in which lung cancer patients received NKT-stimulating injections of dendritic cells that had been pretreated with á-galactosylceramide (á-GalCer)1. Some 60% of treated patients exhibited a striking seven-fold improvement in their median survival time relative to their untreated counterparts. “The effects are superior to other molecular-targeted cancer drugs,” says Masaru Taniguchi of the RIKEN Research Center for Allergy and Immunology (RCAI), Yokohama, whose team participated in this study. “However, this therapy is not applicable to two-thirds of patients because of their limited number of NKT cells.”

To solve this problem, Taniguchi teamed up with RCAI colleague Haruhiko Koseki to develop a method for generating transplantable NKTs2. They derived these from induced pluripotent stem cells (iPSCs), embryonic-like cells that are typically generated via virus-mediated delivery of ‘reprogramming genes’ into skin cells. However, NKT maturation involves a complex genomic rearrangement event, making them difficult to derive from conventional iPSCs. As such, Taniguchi and Koseki devised a novel approach for generating mouse iPSCs from existing NKTs, which have already undergone this rearrangement. They used these iPSCs to generate large numbers of new NKTs in vitro.

Their method efficiently produced mature NKTs, which rapidly established a stable population within the liver upon transplantation into mice. To the researchers’ pleasant surprise, these new NKTs displayed typical activation behavior in response to á-GalCer-treated dendritic cells and proved capable of coordinating an effective immune response. “In general, cells generated from in vitro culture die quickly in vivo or are killed by host immune cells … however, this was not the case here,” says Taniguchi. “We detected iPSC-derived NKT cells with adjuvant activity and tumor-eradicating effects two weeks after cell transfer.”

Taniguchi, Koseki and colleagues are now keen to begin working with human cells. This transition will involve many new challenges, but the researchers see great clinical potential in their approach—particularly in the US, where the Food and Drug Administration has approved development of cell-based therapies. “NKT cell-targeted adjuvant cell therapy is applicable [to] any type of cancer patient, because it can overcome [their] immunodeficient status and enhances antitumor responses,” says Taniguchi. “At present, the delivery of patient dendritic cells is the main limiting factor.”

The corresponding author for this highlight is based at the Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology

Associated links

Link to article
Journal information
1. 1.Motohashi, S., Nagato, K., Kunii, N., Yamamoto, H., Yamasaki, K., Okita, K., Hanaoka, H., Shimizu, N., Suzuki, M., Yoshino, I., et al. A phase I-II study of alpha-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. Journal of Immunology 182, 2492–2501 (2009).

2. 2.Watarai, H., Fujii, S., Yamada, D., Rybouchkin, A., Sakata, S., Nagata, Y., Iida-Kobayashi, M., Sekine-Kondo, E., Shimizu, K., Shozaki, Y. et al. Murine induced pluripotent stem cells can be derived from and differentiate into natural killer T cells. The Journal of Clinical Investigation 120, 2610–2618 (2010).