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 towards acute myeloid leukemia (AML) 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. We here demonstrate in a donor-patient-specific NOD.Cg-Prkdc(scid) IL2rg(tmWjl)/Sz (NSG) xenotransplantation model that NK cells mediate considerable alloreactivity towards pediatric BCP-ALL in vivo. Notably, not only adoptively transferred mature, KIR(+) NK cells but also immature, KIR- NK cells arising early post transplantation in humanized NSG mice (huNSG) exerted substantial anti-leukemic activity. Low-dose and long-term treatment of huNSG mice with the DNA-demethylating agent 5-Aza-cytidine distinctly enhanced the anti-tumor 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.