NK cell receptors and their ligands in leukemia. Leukemia

Department of Hematology, HLA and Molecular Hematology Laboratory, Universitair Ziekenhuis Brussel, Brussels, Belgium.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 03/2008; 22(2):249-57. DOI: 10.1038/sj.leu.2405040
Source: PubMed


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.

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Available from: Christian Demanet, Jul 03, 2014
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    • "Acute myeloid leukemia (AML) is a frequent malignant hematological disease characterized by the initial accumulation of immature leukemia cells in the bone marrow and their subsequent migration into the blood circulation [8]. Natural Killer (NK) cells are key players in the immune surveillance of AML [9], and able to eradicate leukemic cells in an autologous or allogeneic setting [10], [11]. NK cell activity has been positively correlated with relapse-free survival after haematopoietic stem cell transplantation [12], [13]. "
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    ABSTRACT: Integrins are a large family of heterodimeric proteins that are involved in cell adhesion, migration, and proliferation. Integrin diversity and function is regulated by alternative splicing. Membrane-bound and truncated β3-integrins were shown to be key players in cancer metastasis. However, the immunomodulatory functions of the soluble (s) β3-integrin have not been investigated yet. In this study, we described a novel form of sβ3-integrin in acute myeloid leukaemia (AML) patients. Furthermore, we assessed the role of the sβ3-integrin in the modulation of natural killer (NK)-cell activity. Levels of sβ3-integrin were analysed in plasma samples of 23 AML patients and 26 healthy donors by ELISA. The capacity of sβ3-integrin to regulate NK cell activity was investigated using proliferation, cytokine secretion, and cytotoxicity assays. Circulating sβ3-integrin was detected in the plasma of 8 AML patients. NK cells showed significantly higher proliferation rates after stimulation with sβ3-integrin and IL-2, IL-15 (73%). Significant increases in the NK cells' secreted levels of TNF-α, IFN-γ were measured in presence of sβ3-integrin. In addition, sβ3-integrin caused the upregulation of Granzyme B transcripts levels as well as FasL expression levels in NK cells. Most importantly, significantly higher K562 or AML blast target cell lysis rates were observed when NK cells were exposed to sβ3-integrin. This study reports the identification of a novel sβ3-integrin in AML patients and provides novel insights into its role in the immunomodulation of NK cell activity.
    PLoS ONE 06/2014; 9(6):e98936. DOI:10.1371/journal.pone.0098936 · 3.23 Impact Factor
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    • "This finding was related to the high prevalence of the inhibitory KIR2DL2 gene. Another significant association with leukemia was found for two distinct KIR genotypes, which included all inhibitory KIRs (Uhrberg et al., 2002; Verheyden and Demanet, 2008). In a more recent study of pediatric ALL patients, Almalte et al. (2011) reported a highly significant association between the presence of stimulatory KIR genes and decreased risk for ALL. "
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    ABSTRACT: The antileukemic potential of natural killer (NK) cells has been of rising interest in recent years. Interactions between inhibitory killer cell immunoglobulin-like receptors (KIR) and HLA class I ligands seem to be critically involved in the immunosurveillance process. It is also well established that mismatching of HLA class I-encoded KIR ligands in the setting of hematopoietic stem cell transplantation leads to allorecognition of leukemic cells by NK cells, which is in line with the concept of missing-self recognition. Recent data now suggest that KIR gene polymorphism constitutes another important parameter that needs to be taken into account for selection of suitable stem cell donors. Moreover, the role of KIR gene polymorphism for predisposition to leukemia is a current matter of debate. Here, we would like to review the role of KIR function and genetic polymorphism for recognition of leukemia and discuss the impact of these findings for developing novel concepts for NK cell-based immunotherapy strategies.
    Frontiers in Immunology 02/2013; 4:27. DOI:10.3389/fimmu.2013.00027
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    • "phosphatidylserine, calreticulin, heat-shock proteins, high-mobility group box-A protein), that are emitted during immunogenic cell death to facilitate their recognition and phagocytosis by neighbouring immune cells [1], [5], [13]. Analysis of the expression of the activating receptor NKG2D on NK cells and its ligands (MHC class I chain-related (MIC) A/B and UL16 binding proteins (ULBPs)), which are down-regulated or absent on AML cells [32], [44]-[46], could also provide a possible explanation for the improved sensitivity towards NK cells. Finally, mapping the overall cytokine profile of dsRNA-modified tumor cells cocultured with DC and NK cells would be of essential value to further dissect the mechanisms of action. "
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    ABSTRACT: α active specific immunotherapy aims at stimulating the host's immune system to recognize and eradicate malignant cells. The concomitant activation of dendritic cells (DC) and natural killer (NK) cells is an attractive modality for immune-based therapies. Inducing immunogenic cell death to facilitate tumor cell recognition and phagocytosis by neighbouring immune cells is of utmost importance for guiding the outcome of the immune response. We previously reported that acute myeloid leukemic (AML) cells in response to electroporation with the synthetic dsRNA analogue poly(I:C) exert improved immunogenicity, demonstrated by enhanced DC-activating and NK cell interferon-γ-inducing capacities. To further invigorate the potential of these immunogenic tumor cells, we explored their effect on the phagocytic and cytotoxic capacity of DC and NK cells, respectively. Using single-cell analysis, we assessed these functionalities in two- and three-party cocultures. Following poly(I:C) electroporation AML cells become highly susceptible to NK cell-mediated killing and phagocytosis by DC. Moreover, the enhanced killing and the improved uptake are strongly correlated. Interestingly, tumor cell killing, but not phagocytosis, is further enhanced in three-party cocultures provided that these tumor cells were upfront electroporated with poly(I:C). Altogether, poly(I:C)-electroporated AML cells potently activate DC and NK cell functions and stimulate NK-DC cross-talk in terms of tumor cell killing. These data strongly support the use of poly(I:C) as a cancer vaccine component, providing a way to overcome immune evasion by leukemic cells.
    PLoS ONE 06/2011; 6(6):e20952. DOI:10.1371/journal.pone.0020952 · 3.23 Impact Factor
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