Determinants of antileukemia effects of allogeneic natural killer cells

Abstract

In HLA-nonidentical bone marrow transplantation, we sought to determine the characteristics of donor NK cells, recipient leukemia cells, and the cytokine environment that predict the antileukemia effects of allogeneic NK cells. We found that the risk of leukemia relapse in a prospective cohort of 36 pediatric patients was best predicted by a model taking into consideration the presence of inhibitory killer-cell immunoglobulin-like receptors (KIRs) on the donor’s NK cells and the absence of corresponding KIR ligand in the recipient’s HLA repertoire (a receptor-ligand model). The risk of relapse was prognosticated less precisely by the Perugia donor-recipient KIR ligand-ligand mismatch model or by a natural cytotoxicity model. In contrast to the Perugia model, we found that the new receptor-ligand model was accurate when analysis was applied to patients with lymphoid malignancy. These findings corroborate our observations that the recipient’s KIR repertoire, which was derived from highly purified HLA-disparate CD34+ cells, always resumed a donor-specific pattern within 3 months of transplantation but did not correlate evidently with either the donor or recipient ligand repertoire. In an in vitro assay and an in vivo mouse model, human NK-cell cytotoxicity toward human leukemia cells with 11q23 chromosomal rearrangement increased with the number of receptor-ligand mismatch pairs or prestimulation with IL-12 and IL-18. These findings provide new insights into the determinants of antileukemia effects of allogeneic NK cells and therapeutic strategies.