iPSC-Derived iNK Progenitors Engraft and Generate NK Cells in Unconditioned and Autologous Immune Humanized Mice

NK cells exhibit inherently short persistence in vivo. Allo-NK cells trigger host immune rejection in immune-competent patients. Lymphodepletion is a conventional approach for mitigating allogeneic rejection of therapeutic NK cells, which brings host immune suppression and infection risks. To address these problems, we test the concept of engrafting iNK progenitor (iNKP) cells derived from human induced pluripotent stem cells (iPSC) to achieve generating iNK cells in vivo in unconditioned host-immune humanised mice without the requirement for prior lymphodepleting chemotherapy or total body irradiation. Our results showed that a single low-dose infusion of iNKP cells successfully engrafted and continuously produced mature iNK cells in unconditioned B-NDG hIL15 mice. Furthermore, the iPSC-derived iNKP cells survived in the presence of autologous PBMC-humanised mice and generated mature iNK cells. This study provides evidence that autologous iPSC-derived iNKP cells have the application potential for treating the same individual without the preceding necessity of lymphodepletion.