NKG2D Signaling Leads to NK Cell Mediated Lysis of Childhood AML

Schlegel, Patrick; Ditthard, Kerstin; Lang, Peter; Mezger, Markus; Michaelis, Sebastian; Handgretinger, Rupert; Pfeiffer, Mat­thias

doi:10.1155/2015/473175

Cited by 25 publications

(16 citation statements)

References 39 publications

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“…In the absence of a KIR-ligand mismatch, NK cells are capable of killing leukemic blasts with low expression of HLA class I molecules more efficiently than cells with high HLA class I expression. 29,30 Indeed, our analysis of HLA class I expression on primary blasts from patients with acute lymphoblastic leukemia 31 or AML (supplemental Figure 4) showed significantly lower expression on leukemic blasts compared with cells from healthy donors. Thus, we propose that in a setting where cancer cells downregulate HLA class I molecules, the licensing status of NK cells and coexpression of activating KIRs will be the major determinants of alloreactivity.…”

Section: Discussionmentioning

confidence: 84%

Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation

Sekine

Marín

Cao

et al. 2016

Blood

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Key Points• Patients homozygous for HLA-C2 group alleles have worse outcomes after CBT.• CB selection based on the combination of NK licensing and activating KIRs may improve outcomes after CBT.The ability of cord blood transplantation (CBT) to prevent relapse depends partly on donor natural killer (NK) cell alloreactivity. NK effector function depends on specific killer-cell immunoglobulin-like receptors (KIR) and HLA interactions. Thus, it is important to identify optimal combinations of KIR-HLA genotypes in donors and recipients that could improve CBT outcome. We studied clinical data, KIR and HLA genotypes, and NK-cell reconstitution in CBT patients (n 5 110). Results were validated in an independent cohort (n 5 94). HLA-KIR genotyping of recipient germline and transplanted cord blood (CB) grafts predicted for large differences in outcome. Patients homozygous for HLA-C2 group alleles had higher 1-year relapse rate and worse survival after CBT than did HLA-C1/C1 or HLA-C1/C2 (HLA-C1/x) patients: 67.8% vs 26.0% and 15.0% vs 52.9%, respectively. This inferior outcome was associated with delayed posttransplant recovery of NK cells expressing the HLA-C2-specific KIR2DL1/S1 receptors. HLA-C1/x patients receiving a CB graft with the combined HLA-C1-KIR2DL2/L3/S2 genotype had lower 1-year relapse rate (6.7% vs 40.1%) and superior survival (74.2% vs 41.3%) compared with recipients of grafts lacking KIR2DS2 or HLA-C1. HLA-C2/C2 patients had lower relapse rate (44.7% vs 93.4%) and better survival (30.1% vs 0%) if they received a graft with the combined HLA-C2-KIR2DL1/S1 genotype. Relapsed/ refractory disease at CBT, recipient HLA-C2/C2 genotype, and donor HLA-KIR genotype were independent predictors of outcome. Thus, we propose the inclusion of KIR genotyping in graft selection criteria for CBT. HLA-C1/x patients should receive an HLA-C1-KIR2DL2/L3/ S2 CB graft, while HLA-C2/C2 patients may benefit from an HLA-C2-KIR2DL1/S1 graft. (Blood. 2016;128(2):297-312)

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Section: Discussionmentioning

confidence: 84%

Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation

Sekine

Marín

Cao

et al. 2016

Blood

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“…The name “natural killer cell” originally came from their ability to kill tumor cells in vitro and in vivo without previous stimulation ( 22 , 28 – 31 ). Their antitumor activity includes activity against acute lymphoblastic leukemia ( 32 ), acute myeloid leukemia ( 33 ), and neuroblastoma ( 34 , 35 ). In addition to their antitumor activity, NK cells play an important role in the host response against various pathogens which includes viruses such as cytomegalovirus (CMV), Epstein–Barr virus ( 23 , 36 – 38 ), or hepatitis B and C virus ( 37 , 39 , 40 ), and Gram-positive, Gram-negative, and intracellular bacteria, such as Salmonella typhi, Escherichia coli ( 41 ), or Listeria monocytogenes ( 42 ).…”

Section: Nk Cell Biologymentioning

confidence: 99%

Natural Killer Cells in Antifungal Immunity

2017

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Invasive fungal infections are still an important cause of morbidity and mortality in immunocompromised patients such as patients suffering from hematological malignancies or patients undergoing hematopoietic stem cell transplantion. In addition, other populations such as human immunodeficiency virus-patients are at higher risk for invasive fungal infection. Despite the availability of new antifungal compounds and better supportive care measures, the fatality rate of invasive fungal infection remained unacceptably high. It is therefore of major interest to improve our understanding of the host–pathogen interaction to develop new therapeutic approaches such as adoptive immunotherapy. As experimental methodologies have improved and we now better understand the complex network of the immune system, the insight in the interaction of the host with the fungus has significantly increased. It has become clear that host resistance to fungal infections is not only associated with strong innate immunity but that adaptive immunity (e.g., T cells) also plays an important role. The antifungal activity of natural killer (NK) cells has been underestimated for a long time. In vitro studies demonstrated that NK cells from murine and human origin are able to attack fungi of different genera and species. NK cells exhibit not only a direct antifungal activity via cytotoxic molecules but also an indirect antifungal activity via cytokines. However, it has been show that fungi exert immunosuppressive effects on NK cells. Whereas clinical data are scarce, animal models have clearly demonstrated that NK cells play an important role in the host response against invasive fungal infections. In this review, we summarize clinical data as well as results from in vitro and animal studies on the impact of NK cells on fungal pathogens.

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“…1,2 The ability of NK cells to eliminate AML has been demonstrated in vitro and also through clinical observations in haploidentical allogeneic hematopoietic stem cell transplantation (alloHSCT), where the presence of killer immunoglobulin receptor (KIR) ligand mismatch in the graft-versus-host direction confers enhanced protection against AML relapse. [3][4][5][6] NK cell activity is modulated by a number of germ-line encoded inhibitory and activating receptors. The interaction between HLA class I molecules on target cells and KIR or the lectin heterodimer CD94/natural killer group 2 member A delivers an inhibitory signal to NK cells, and the corollary of this is observed where the lack of HLA class I expression (ie, "missing self") on tumor cells allows NK cells to detect and kill malignant transformed cells.…”

Section: Introductionmentioning

confidence: 99%

Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy

Mastaglio¹,

Wong

Perera

et al. 2018

Blood Advances

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Natural killer (NKs) cells provide rapid responses to viral-infected and malignant cells, including acute myeloid leukemia (AML) blasts. The balance among inhibitory and activating signals, delivered by multiple interactions between ligands on target cells and NK receptors, determines the posture of the NK cell response to either one of target cell elimination or tolerance. The aim of this work was to study the influence of the differential expression of activating and inhibitory NK receptor ligands (NKRLs) by leukemic blasts on clinical outcome in newly diagnosed AML patients. Leukemic cells and clinical data from 66 patients undergoing induction chemotherapy were obtained from the Australasian Leukemia Lymphoma Group tissue bank. Expression of 6 activating (MICA, MICAB, CD155, CD112, ULBP1, and ULBP2/5/6) and 3 inhibitory (HLA class I, PD-L1, and PD-L2) NKRLs was analyzed by flow cytometry. AML blasts displayed heterogeneous expression of NKRLs. MICA, CD112, and ULBP1 were most frequently expressed. ULBP1 expression was significantly associated with improved 2-year overall survival (51.4% vs 11.4%), relapse-free survival (42.5% vs 10.0%), and reduced relapse (44.1% vs 78.6%). We calculated a net score of activating minus inhibitory ligands and demonstrated that the expression of an overall activating NK ligand phenotype was associated with superior 2-year overall survival (59.6% vs 24.4%) and reduced relapse (31.5% vs 68.2%). Our study provides clinical evidence for the role of NK cell-mediated immunoediting against AML, mediated by the expression of NKRLs on blasts, and supports investigation into strategies to enhance NK cell function to improve outcomes in patients with AML.

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NKG2D Signaling Leads to NK Cell Mediated Lysis of Childhood AML

Cited by 25 publications

References 39 publications

Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation

Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation

Natural Killer Cells in Antifungal Immunity

Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy

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