Journal
STEM CELLS
Volume 34, Issue 12, Pages 2852-2860Publisher
WILEY-BLACKWELL
DOI: 10.1002/stem.2465
Keywords
Invariant NKT cells; NK cells; Induced pluripotent stem cells; Reprogramming; Immunotherapy
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Funding
- Research Center Network for Realization of Regenerative Medicine from Japan Agency for Medical Research and Development (AMED)
- CREST, Japan Science and Technology Agency
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Reprogramming of antigen-specific T lymphocytes into induced pluripotent stem cells (iPSCs) and their subsequent re-differentiation has enabled expansion of functional T lymphocytes in vitro, thus opening up new approaches for immunotherapy of cancer and other diseases. In this study, we have established a robust protocol to reprogram human invariant NKT (V alpha 24(+) iNKT) cells, which have been shown to act as cellular adjuvants and thus exert anti-tumor activity in mice and humans, and to re-differentiate the iNKT cell-derived iPSCs into functional iNKT cells. These iPSC-derived iNKT cells (iPS-V alpha 24(+) iNKT cells) can be activated by ligand-pulsed dendritic cells (DCs) and produce a large amount of interferon-c upon activation, as much as parental V alpha 24(+) iNKT cells, but exhibit even better cytotoxic activity against various tumor cell lines. The iPS-V alpha 24(+) iNKT cells possess significant anti-tumor activity in tumor-bearing mice and can activate autologous NK cells upon activation by ligand-pulsed DCs in the NOG mouse model in vivo, further extending their therapeutic potential. This study thus provides a first proof of concept for the clinical application of human iPS-V alpha 24(+) iNKT cells for cancer immunotherapy.
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