IntroductionImproved outcome of acute myeloid leukemia (AML) after stemcell transplantation across the human leukocyte antigen (HLA) class I barrier highlighted a potential of natural killer (NK) cells in recognition and elimination of residual malignant cells by the graft-versus-leukemia (GVL) effect in the absence of graft-versushost disease (GVHD). 1,2 NK cells develop rapidly from transplanted progenitor cells but display numerous phenotypic abnormalities and a functional immaturity, which may limit their effectiveness in tumor rejection in vivo. 3,4 Adoptive transfer of mature NK cells in the early posttransplantation period is therefore a rational approach aimed at providing the patient with the benefit of competent cytotoxic effectors. 5 NK cells are innate immunity CD56 ϩ CD3 Ϫ lymphocytes, the function of which is regulated by the integration of signals delivered from multiple inhibitory and activating receptors. 6 The killer immunoglobulin-like receptors (KIRs), which are clonally distributed in the NK-cell repertoire, recognize allelic groups of HLA class I molecules on target cells and are dominant determinants of NK-cell function. 7 NK cytotoxicity is inhibited on recognition of "self" HLA class I molecules, whereas absence or loss of HLA class I can render cells susceptible to NK-mediated lysis. In the transplant setting from haploidentical stem-cell donor, alloreactivity of NK cells is provided by the KIR-HLA class I mismatch. 8 In addition to sensing the missing self HLA class I molecules, NK cells need to be stimulated through engagement of activating NK receptors by specific cell-surface ligands expressed by target cells. 9,10 NKG2D is one of the best characterized receptors required for NK-mediated tumor immunosurveillance. 11 In mice, NKG2D function can protect the host from tumor initiation and also eradicate existing tumors expressing the H60 and Rae-1 ligands. 12,13 The human NKG2D ligands (NKG2D-L) include 2 families of proteins belonging to major histocompatibility complex class I (MIC)-related molecules, and UL-16 binding proteins (ULBP). 14,15 In epithelial tissue, the surface expression of NKG2D-L is up-regulated in response to cellular stress, including heat shock, DNA damage, and stalled DNA replication, which are common in human cancer. 16,17 A notion that NKG2D-L play a key role as tumor-associated ligands rendering cells susceptible to NK-mediated lysis, has encouraged pharmacologic approaches to achieve the NKG2D-L induction. 18,19 Understanding the molecular interactions regulating the NK function has uncovered numerous escape mechanisms preventing recognition of leukemic blasts by NK cells. Unlike in solid tumors, which frequently down-regulate HLA class I molecules, malignant leukemic cells carry high levels of HLA class I having a protective effect. 20 NKG2D-L are absent or expressed at low levels in the majority of patients with acute leukemia, 21-23 thereby preventing efficient activating interactions. An additional route of tumor The online version of this article contain...

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Natural killer (NK) cells are implicated in the surveillance of hematological malignancies. They participate in the immune response against residual acute myeloid leukemia (AML) after hematopoietic stem cell transplantation with partial HLA class I disparity. However, the role of NK cells in autologous leukemia-specific immunity remains poorly understood. We studied the function of NK cells in AML patients at diagnosis. Following isolation, CD56+CD3- cells exhibited a high proliferative potential in vitro in response to interleukin (IL)-2. The polyclonal population of activated AML-NK cells expressed normal levels of the activating receptor NKG2D and the major natural cytotoxicity receptor NKp46. AML-NK cells were highly effective with respect to interferon-gamma production, cytotoxicity against HLA class I-deficient K562 erythroleukemia cells in vitro and retardation of tumor growth in vivo in K562-bearing NOD/SCID mice. Importantly, when AML blasts were injected into NOD/SCID mice, a single dose of adoptively transferred autologous AML-NK cells significantly reduced the AML load by 8-77%. Recognition of AML blasts may be related to the observed upregulation of ligands for NKG2D and natural cytotoxicity receptors in vivo. We conclude that AML patient-derived NK cells are fully functional, in support of exploring the benefit of AML immunotherapy with IL-2-stimulated autologous NK cells.