Relapse after allo-SCT in patients with acute leukaemia remains a major problem. A beneficial impact of alloreactive natural killer (NK) cells has been reported for myeloid malignancies, but has been questionable for B-lineage ALL. We analysed lysis of primary paediatric precursor-B-ALL blasts by 285 NK cell clones to investigate whether HLA class I expression on the blasts and phenotypic killer cell Ig-like receptor (KIR) expression on NK cells affect the lytic activity against ALL blasts. Precursor-B-ALL blasts with low HLA-I expression were lysed by a majority (79%) of NK cell clones, whereas those with high HLA-I expression showed low susceptibility to NK clones independent of their KIR expression patterns. NK cell activity against susceptible blasts was regulated by differential surface expression of the three major KIRs (CD158a, CD158b, CD158e). NK clones with none of these three KIRs or a single KIR that recognized no ligand, were not inhibited by the targets and exerted higher lysis (P ¼ o0.0005) in comparison to NK clones expressing KIRs with a ligand on the ALL blasts. In conclusion, the quantity of HLA-I expression on precursor-B-ALL blast regulates overall NK cell susceptibility; in case of reduced HLA expression, differential surface expression of KIRs affects NK cell alloreactivity against those blasts.
Relapse after allogeneic stem cell transplantation of patients with acute lymphoblastic leukemia (ALL) remains a major problem. A beneficial impact of alloreactive NK cells has been reported for myeloid malignancies, but has been questionable for B-lineage-ALL. Here we show that the majority of NK cell clones from healthy donors could effectively lyse primary blasts from a representative childhood precurser-B-ALL and demonstrate the relevance of differential surface expression of KIRs (killer cell immunglobulin like receptors CD158a, CD158b and CD158e) for antileukemic alloreactivity. More than 79% of clones exerted specific lysis >40% against primary ALL blasts. Mismatch of effector/target HLA-C type (KIR-ligand incompatibility) did not correlate with antileukemic alloreactivity, although non-malignant lymphoblastoid cell lines were lysed according to KIR-ligand incompatibility. In contrast differential surface expression of the three major KIRs showed significant impact on the antileukemic activity against precursor-B-ALL blasts. NK clones with none of the three KIRs or a single KIR that recognized no ligand, were not inhibited by the targets and exerted higher lysis (p = <0.03) in comparison to NK clones with expression of one or more KIRs with a ligand on the ALL blasts. In conclusion the differential surface expression of KIRs is relevant to predict NK cell activity against childhood lymphoid leukemia.
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