Both mature KIR+ and immature KIR− NK cells control pediatric acute B-cell precursor leukemia in NOD.Cg-Prkdcscid IL2rgtmWjl/Sz mice

Therapeutic natural killer (NK)-cell–mediated alloreactivity toward acute myeloid leukemia has largely been attributed to mismatches between killer immunoglobulin-like receptors (KIRs) on NK cells and their ligands, HLA class I molecules, on target cells. While adult acute B-cell precursor leukemia (BCP-ALL) appears to be resistant to NK-cell–mediated lysis, recent data indicate that pediatric BCP-ALL might yet be a target of NK cells. In this study, we demonstrate in a donor-patient–specific NOD.Cg-PrkdcscidIL2rgtmWjl/Sz (NSG) xenotransplantation model that NK cells mediate considerable alloreactivity toward pediatric BCP-ALL in vivo. Notably, both adoptively transferred mature KIR+ NK cells and immature KIR− NK cells arising early posttransplantation in humanized NSG mice exerted substantial antileukemic activity. Low-dose and long-term treatment of humanized NSG mice with the DNA-demethylating agent 5-aza-cytidine distinctly enhanced the antitumor response, interestingly without inducing common inhibitory KIR expression but rather by promoting the differentiation of various NK-cell precursor subsets. Collectively, these data indicate that the future design of innovative therapy protocols should consider further exploitation of NK-cell–mediated immune responses for poor prognosis pediatric BCP-ALL patients. •Both mature KIR+ and immature KIR− NK cells exert antileukemic activity toward pediatric BCP-ALL in vivo.•In vivo treatment with low-dose 5-aza-cytidine enhances immature and mature NK-cell counts and promotes antitumor response.