NK cell receptors and their ligands in leukemia

Abstract

Human natural killer (NK) cells are built to kill abnormal cells but to preserve autologous normal cells. To accomplish this task, they are equipped with a large number of inhibiting and activating receptors. Ligation with corresponding ligands will determine whether the NK cell becomes activated to destroy the abnormal cell. This review will focus on the abnormalities of NK cell receptors and their putative ligands found in patients with leukemia, which can lead to an inadequate function of NK cells allowing these malignant cells to escape from NK cell destruction. In recent years it has become clear that NK cells in the haploidentical hematopoietic stem cell transplantation (HSCT) setting are very effective in eliminating residual acute myeloid, but not acute lymphoid, leukemic cells. In this regard, we also reviewed published studies of retrospective cohorts of HSCT investigating the potential beneficial effect of killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) ligands on NK alloreactivity. Manipulating NK cell inhibition or activation could lead to new forms of immunotherapy, ultimately leading to the elimination of resistant leukemic cells.

Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies

“…This may suggest a failure to express some NK ligands on B-CLL cells, such as MICA and ULBPs, as previously reported. 25 In contrast, the major phenotypic alterations in NK cells observed in acute leukemia, including the downregulation of natural cytotoxicity receptors, 26,27 suggest that chronic and acute leukemia use NK cells and optimized anti-CD20 in CLL M Le Garff-Tavernier et al different strategies to escape from NK-cell immunity. Poor expression of CD69 was also observed on CD16 þ CD56 dim NK cells from CLL patients; this deficit could explain the previously reported reduction in NK cytotoxic activity in the absence of exogenous stimulation.…”

Natural killer cell immune escape in acute myeloid leukemia

“…[32][33][34][35][36][37][38] Results of those studies are discussed in more detail elsewhere by Verheyden and Demanet. 39 Another NK cell escape mechanism demonstrated in the HSCT setting is the overexpression of the inhibitory receptor CD94/ NKG2A on reconstituted NK cells that recognizes human leukocyte antigen-E on AML blasts, which is associated with a low cytotoxic capacity. 40,41 AML cells themselves contribute to impaired NK cell-mediated killing by decreased or absent expression of surface ligands for various NK cell activating receptors, including NCRs and NKG2D.…”

“…Several cytokines have been described to affect the expression of NK cell activating receptors and activity of NK cells. 39,83,84 For example IFN-a, which has already been demonstrated to exert beneficial effects in AML patients 85,86 and to be a promoter of NK cell-mediated killing, upregulates the activating NKG2D receptor [87][88][89][90] and downregulates the inhibitory NKG2A receptors. 88 NKG2D and NCR expression in AML patients was also shown to be upregulated by IL-15, 26 a currently attractive therapeutic cytokine against AML 91 with strong NK-DC crosstalk potency.…”

KIR genes and KIR ligands affect occurrence of acute GVHD after unrelated, 12/12 HLA matched, hematopoietic stem cell transplantation

“…15 However, all described observations apply to distinct patient groups, and differ substantially depending on transplant protocols, as reviewed recently by Verheyden and Demanet. 16 The purpose of this study was to analyze the association of patient and donor KIR ligands, KIR genes and haplotypes on acute and chronic GVHD (cGVHD), transplant-related mortality (TRM), relapse and OS of 124 adult patients with hematological diseases transplanted at our center. Patients' and donors' characteristics are shown in Table 1.…”