IL‐12/IL‐18‐preactivated donor NK cells enhance GVL effects and mitigate GvHD after allogeneic hematopoietic stem cell transplantation

Adoptive transfer of donor NK cells has the potential of mediating graft-versus-leukemia (GVL) effect while suppressing acute graft-versus-host-disease (aGVHD) during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these beneficial effects are limited by the transient function of adoptively transferred NK cells. Previous studies demonstrate that cytokine-induced memory-like NK cells that are preactivated by IL-12, IL-15, and IL-18 have enhanced effector functions and long life span in vivo. Here, we investigated the effects of IL-12/18-preactivated and IL-12/15/18-preactivated donor NK cells on GVL and aGVHD in a murine model of allo-HSCT. We found that both IL-12/18- and IL-12/15/18-preactivated NK cells mediated stronger GVL effect than control NK cells mainly due to their elevated activation/cytotoxicity and sustained proliferative potential. Interestingly, we observed that although both IL-12/18- and IL-12/15/18-preactivated NK cells significantly inhibited severe aGVHD, only the IL-12/18-preactivated NK cells maintained the beneficial effect of donor NK cells on mild aGVHD. The IL-12/15/18-preactivated NK cell infusion accelerated aGVHD in the fully-mismatched mild aGVHD model. Our results demonstrated that IL-12/18-preactivated NK cells displayed sustained and enhanced GVL functions, and could mitigate aGVHD despite the severity of the disease. IL-12/18-preactivated donor NK cell infusion may be an effective and safe adoptive therapy after allo-HSCT.