Article

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

Stem Cell Allotransplantation Section, Hematology Branch, National Heart Lung and Blood Institute, Department of Transfusion Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Blood (Impact Factor: 9.78). 12/2005; 106(10):3666-72. DOI: 10.1182/blood-2005-02-0479
Source: PubMed

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.

Download full-text

Full-text

Available from: Hiroshi Fujiwara, Jun 17, 2015
0 Followers
 · 
65 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alloreactive NK cells play a role in tumor eradication after allogeneic HLA mismatched stem cell transplantation (SCT). The effect of NK alloreactivity in HLA identical SCT is still under debate and in particular in transplantation for chronic myeloid leukemia (CML) the data are very limited and with conflicting outcome. The aim of our study was to evaluate the effect of KIR genes and KIR ligands on leukemia free survival (LFS) and relapse rate in a well-defined, homogeneous group of CML patients phase upon HLA identical sibling SCT. We retrospectively analyzed the effect of KIRs and KIR ligands (C1 and C2) on LFS and relapse in 70 CML patients in 1st chronic phase, who had received an HLA identical sibling graft. For KIR typing we used a single PCR based KIR typing protocol that also included primers allowing for the identification of the KIR binding site on HLA-Cw (AA 77 and 80). The data show clear differences in transplant outcome between patients having both ligands (C1 and C2) as compared to patients having only one ligand (C1 or C2). In the latter group, the stimulatory KIR2DS5 gene was associated with improved leukemia free survival (p=0.007; hazard ratio 4.3; 95% confidence interval 1.3-6.7) and lower relapse rates (p=0.028; HR 4.3, 95% CI 1.1-9.1). In contrast, in patients carrying both ligands, KIR2DS5 was associated with reduced LFS (p=0.0056; HR 0.3; 95% CI 0.1-0.7) and higher relapse rate (p=0.02; HR 0.35, 95% CI 0.1-0.8). Our data indicate a role for an NK mediated anti-CML response after HLA identical sibling SCT that is influenced by KIR ligands and, more importantly, by stimulatory KIRs present in the donor.
    Molecular Immunology 09/2008; 45(13):3631-8. DOI:10.1016/j.molimm.2008.04.016 · 3.00 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The activating immunoreceptor NKG2D (natural killer group 2, member D) and its ligands play important roles in the innate and adaptive immune responses. UL16-binding protein 3 (ULBP3), an NKG2D ligand, is overexpressed on certain epithelial tumor cells. In this study, we investigated the effect of ULBP3 expression on the cytotoxic activity of natural killer (NK) cells. ULBP3 were measured by flow cytometry analysis, immunohistochemistry, and time-resolved fluoroimmunoassay. The cytotoxicity of NK cells was determined with the lactate dehydrogenase release assay. We found that ULBP3 was overexpressed on tumor cell lines and tumor tissues. Serum from cancer patients, but not from healthy donors, contained elevated levels of soluble ULBP3 (sULBP3). Importantly, high expression of ULBP3 on the cell surface of tumor cells augmented NKG2D-mediated NK cell cytotoxicity. However, low levels of sULBP3 (<15 ng/ml) weakened the cytotoxicity of NK cells by decreasing NKG2D expression on NK cells. Further analysis showed that serum samples from most cancer patients (>70%) contained the low level of sULBP3. Our results demonstrate that tumor cells express surface and soluble ULBP3, which regulate NK cell activity. Thus, ULBP3 is a potential therapeutic target for improving the immune response against cancer.
    Scientific Reports 08/2014; 4:6138. DOI:10.1038/srep06138 · 5.08 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although natural killer (NK) cells can be readily generated for adoptive therapy with current techniques, their optimal application to treat malignant diseases requires an appreciation of the dynamic balance between signals that either synergize with or antagonize each other. Individuals display wide differences in NK function that determine their therapeutic efficacy. The ability of NK cells to kill target cells or produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. The selection of NK cells with a predominant activating profile is critical for delivering successful anti-tumor activity. This can be achieved through selection of killer immunoglobulin-like receptor-mismatched NK donors and by use of blocking molecules against inhibitory pathways. Optimum NK cytotoxicity may require licensing or priming with tumor cells. Recent discoveries in the molecular and cellular biology of NK cells inform in the design of new strategies, including adjuvant therapies, to maximize the cytotoxic potential of NK cells for adoptive transfer to treat human malignancies.
    Cytotherapy 05/2014; 16(11). DOI:10.1016/j.jcyt.2014.03.009 · 3.10 Impact Factor