The antileukemia effect of HLA-matched NK and NK-T cells in chronic myelogenous leukemia involves NKG2D–target-cell interactions

Abstract

To study natural killer (NK) cell–mediated antileukemic activity in chronic myelogenous leukemia (CML), we investigated the ability of HLA-matched and mismatched CD56⁺ cells to inhibit granulocyte macrophage–colony-forming unit (CFU-GM) formation by leukemic CD34⁺ cells. In 14 HLA-identical donor-recipient pairs, donor CD56⁺ cells inhibited CML CFU-GM comparably to effectors from 14 HLA-mismatched unrelated individuals (mean inhibition 42% ± 9% vs 39.5% ± 7% at a 10:1 effector-to-target (E/T) ratio), suggesting that killer inhibitory receptor (KIR) incompatibility was not essential for an antileukemic effect. Both CD56⁺CD3^- (natural killer [NK]) and CD56⁺CD3⁺(NK-T) cells inhibited CFU-GM growth of CML but not normal CD34⁺ cells. A mechanism for this leukemia-specific cytotoxicity was suggested by the abnormal overexpression of major histocompatibility class I chain–related gene A or gene B (MICA/B) on CML CD34 cells and their ability to bind the NK activation ligand NKG2D. However, in vivo, CML cells may avoid NK-cell–mediated immune destruction by immune escape, shedding MICA into the plasma, thereby down-regulating NKG2D on CML CD56⁺ cells.