scholarly journals Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Sara Petillo ◽  
Cristina Capuano ◽  
Rosa Molfetta ◽  
Cinzia Fionda ◽  
Abdelilah Mekhloufi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Membrane ◽  
Natural Killer ◽  
Nk Cell ◽  
Hematologic Malignancy ◽  
Mrna Level ◽  
Killer Cell ◽  
Mrna Levels ◽  
Cell Recognition ◽  
Nkg2d Ligands

AbstractMultiple Myeloma (MM) is an incurable hematologic malignancy of terminally differentiated plasma cells (PCs), where immune interactions play a key role in the control of cancer cell growth and survival. In particular, MM is characterized by a highly immunosuppressive bone marrow microenvironment where the anticancer/cytotoxic activity of Natural Killer (NK) cells is impaired. This study is focused on understanding whether modulation of neddylation can regulate NK cell-activating ligands expression and sensitize MM to NK cell killing. Neddylation is a post-translational modification that adds a ubiquitin-like protein, NEDD8, to selected substrate proteins, affecting their stability, conformation, subcellular localization, and function. We found that pharmacologic inhibition of neddylation using a small-molecule inhibitor, MLN4924/Pevonedistat, increases the expression of the NK cell-activating receptor NKG2D ligands MICA and MICB on the plasma membrane of different MM cell lines and patient-derived PCs, leading to enhanced NK cell degranulation. Mechanistically, MICA expression is upregulated at mRNA level, and this is the result of an increased promoter activity after the inhibition of IRF4 and IKZF3, two transcriptional repressors of this gene. Differently, MLN4924/Pevonedistat induced accumulation of MICB on the plasma membrane with no change of its mRNA levels, indicating a post-translational regulatory mechanism. Moreover, inhibition of neddylation can cooperate with immunomodulatory drugs (IMiDs) in upregulating MICA surface levels in MM cells due to increased expression of CRBN, the cellular target of these drugs. In summary, MLN4924/Pevonedistat sensitizes MM to NK cell recognition, adding novel information on the anticancer activity of neddylation inhibition.

scholarly journals The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function

2020 ◽  
Vol 117 (21) ◽  
pp. 11636-11647 ◽  
Author(s):  
Philippa M. Saunders ◽  
Bruce J. MacLachlan ◽  
Phillip Pymm ◽  
Patricia T. Illing ◽  
Yuanchen Deng ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Peptide Binding ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Cell Recognition ◽  
Leukocyte Antigen ◽  
Binding Cleft

Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations.

scholarly journals Inhibition of Enhancer of zeste homolog 2 (EZH2) induces natural killer cell-mediated eradication of hepatocellular carcinoma cells

2018 ◽  
Vol 115 (15) ◽  
pp. E3509-E3518 ◽  
Author(s):  
Suresh Bugide ◽  
Michael R. Green ◽  
Narendra Wajapeyee
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Down Regulation ◽  
Nkg2d Ligands ◽  
Enhancer Of Zeste

Natural killer (NK) cell-mediated tumor cell eradication could inhibit tumor initiation and progression. However, the factors that regulate NK cell-mediated cancer cell eradication remain unclear. We determined that hepatocellular carcinoma (HCC) cells exhibit transcriptional down-regulation of NK group 2D (NKG2D) ligands and are largely resistant to NK cell-mediated eradication. Because the down-regulation of NKG2D ligands occurred at the transcriptional level, we tested 32 chemical inhibitors of epigenetic regulators for their ability to re-express NKG2D ligands and enhance HCC cell eradication by NK cells and found that Enhancer of zeste homolog 2 (EZH2) was a transcriptional repressor of NKG2D ligands. The inhibition of EZH2 by small-molecule inhibitors or genetic means enhanced HCC cell eradication by NK cells in a NKG2D ligand-dependent manner. Collectively, these results demonstrate that EZH2 inhibition enhances HCC eradication by NK cells and that EZH2 functions, in part, as an oncogene by inhibiting immune response.

scholarly journals Sensitizing primary acute lymphoblastic leukemia to natural killer cell recognition by induction of NKG2D ligands

2012 ◽  
Vol 54 (1) ◽  
pp. 167-173 ◽  
Author(s):  
Laura Jardine ◽  
Sophie Hambleton ◽  
Venetia Bigley ◽  
Sarah Pagan ◽  
Xiao-Nong Wang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Natural Killer Cell ◽  
Natural Killer ◽  
Lymphoblastic Leukemia ◽  
Killer Cell ◽  
Cell Recognition ◽  
Nkg2d Ligands

scholarly journals The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti–PD-1 antibody

Blood ◽  
2010 ◽  
Vol 116 (13) ◽  
pp. 2286-2294 ◽  
Author(s):  
Don M. Benson ◽  
Courtney E. Bakan ◽  
Anjali Mishra ◽  
Craig C. Hofmeister ◽  
Yvonne Efebera ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune Response ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Immune Response ◽  
Cell Versus

Abstract T-cell expression of programmed death receptor-1 (PD-1) down-regulates the immune response against malignancy by interacting with cognate ligands (eg, PD-L1) on tumor cells; however, little is known regarding PD-1 and natural killer (NK) cells. NK cells exert cytotoxicity against multiple myeloma (MM), an effect enhanced through novel therapies. We show that NK cells from MM patients express PD-1 whereas normal NK cells do not and confirm PD-L1 on primary MM cells. Engagement of PD-1 with PD-L1 should down-modulate the NK-cell versus MM effect. We demonstrate that CT-011, a novel anti–PD-1 antibody, enhances human NK-cell function against autologous, primary MM cells, seemingly through effects on NK-cell trafficking, immune complex formation with MM cells, and cytotoxicity specifically toward PD-L1+ MM tumor cells but not normal cells. We show that lenalidomide down-regulates PD-L1 on primary MM cells and may augment CT-011's enhancement of NK-cell function against MM. We demonstrate a role for the PD-1/PD-L1 signaling axis in the NK-cell immune response against MM and a role for CT-011 in enhancing the NK-cell versus MM effect. A phase 2 clinical trial of CT-011 in combination with lenalidomide for patients with MM should be considered.

scholarly journals IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect

Blood ◽  
2011 ◽  
Vol 118 (24) ◽  
pp. 6387-6391 ◽  
Author(s):  
Don M. Benson ◽  
Courtney E. Bakan ◽  
Shuhong Zhang ◽  
Shauna M. Collins ◽  
Jing Liang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Allogeneic Transplantation ◽  
Cell Receptor ◽  
Phase 2 Trial ◽  
Cell Versus

Abstract Multiple myeloma (MM) patients who receive killer cell Ig–like receptor (KIR) ligand–mismatched, T cell–depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand–matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.

scholarly journals Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells

2016 ◽  
Vol 5 (10) ◽  
pp. e1218105 ◽  
Author(s):  
Fabrizio Antonangeli ◽  
Alessandra Soriani ◽  
Biancamaria Ricci ◽  
Andrea Ponzetta ◽  
Giorgia Benigni ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Natural Killer Cell ◽  
Natural Killer ◽  
Killer Cell ◽  
Cell Recognition ◽  
Drug Induced ◽  
Myeloma Cells

scholarly journals SDF-1α Reduces Human Natural Killer Cell Cytotoxicity against Chronic Myelogenous Leukemia K562 Cells

2019 ◽  
Author(s):  
Alireza Mardomi ◽  
Hadi Hossein-Nataj ◽  
Narjes Jafari ◽  
Nabiallah Mohammadi ◽  
Saeid Abediankenari
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Killer Cell ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
Mrna Levels ◽  
Human Natural Killer Cell ◽  
Natural Killer Cell Cytotoxicity

Stromal cell-derived factor-1 alpha (SDF-1α) has been shown to be up-regulated in a variety of malignancies. So that, its expression is associated with poor prognosis and invasiveness. Natural killer (NK) cells are important effector cells against virus-infected and transformed cells. Especially they play a key role in tumor immune surveillance. Whereas it was not well understood whether SDF-1α modulates anti-tumor immune response or not, the purpose of the present study was to investigate the effect of SDF-1α on the cytotoxic properties of peripheral blood NK cells. Human peripheral blood NK cells were freshly isolated using MACSxpess system and cultured in the presence or absence of recombinant human SDF-1α or SDF-1α plus CXCR4 antagonist, AMD3100. CD107a degranulation assay was conducted through the co-culture of NK cells with K562 cells. The percentage of CD107a positive cells was assessed by flowcytometry. Effect of SDF-1α was also examined on the mRNA levels of NKG2A and NKG2D as indicator examples of NK cell inhibitory and activating receptors, respectively. SDF-1α significantly decreased the degranulation activity of NK cells (p=0.04). The mRNA content of NKG2D was down-regulated under the influence of SDF-1α (p=0.03). Moreover, AMD3100 exhibited a trend in recovering the NKG2D mRNA level to its un-treated state (p=0.05).  The present study reveals that SDF-1α has a negative impact on NK cell activity and might is involved in tumor immune-suppression. Thus, it can be concluded that microenvironment manipulations targeting SDF-1α may reinforce current cancer therapies by disturbing one of the immune-suppressive axes in the cancerous milieu. 

Expression of Activating Natural Killer Cell Receptor Ligands in Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4478-4478
Author(s):  
Ulrike Mura ◽  
Matthias Pfeiffer ◽  
Rupert Handgretinger ◽  
Peter J. Lang
Keyword(s):  
Flow Cytometry ◽  
Natural Killer ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Killer Cell ◽  
Negative Control ◽  
Target Cells ◽  
Nkg2d Ligands ◽  
Ligand Expression

Abstract Activating and inhibitory cell surface receptors regulate natural killer (NK) cell effector functions. The extent of expression of their activating ligands on target cells probably plays a critical role in tumor immune surveillance, but the data of this expression on blasts of leukemia patients are still poor. We examined blasts of children with ALL for the activating human NKG2D ligands MICA, MICB, ULBP1, ULBP2 and ULBP3, and for the ligands of the activating human natural cytotoxic receptors (NCRs) NKp30, NKp44 and NKp46. Using ligand specific mouse monoclonal antibodies and flow cytometry, we screened 24 children (23 common-ALL, one pre-T-ALL) for the expression of NKG2D ligands and 15 children (all common-ALL) for NCR ligands. In 13 patients (all common-ALL), also the density of the NKG2D ligands was determined by quantitative flow cytometry. Considering cells positive for a particular ligand in case of a two fold increase of median fluorescence above negative control, 38 percent of the patients were positive for one or more NKG2D ligands, while only 13 percent expressed one or more NCR ligands at significant levels. ULBP1 was most frequently expressed (29 percent of patients positive), while no patients were positive for ULBP2 and NKp44 ligands. ULBP3 was positive in 17 percent of the patients, NKp30 and NKp46 ligands in 13 percent, MICA and MICB in 4 percent. The patient with pre-T-ALL was positive only for ULBP1. So ULBP1 was expressed more frequently, while the other NKG2D ligands were expressed less frequently in children than reported for adult leukemia patients before (Salih et al. Blood.2003;102:1389–1396.). The density of detected NKG2D ligand molecules was always rather low. For MICA the maximum were 1700 molecules per cell in a single patient, for MICB 900, for ULBP1 1100, and for ULBP3 1000 molecules per cell. In summary, blasts of pediatric ALL patients displayed low or negative surface levels of ligands for the human activating NK cell receptors NKG2D, NKp30, NKp44 and NKp46. QUALITATIVE LIGAND EXPRESSION QUALITATIVE LIGAND EXPRESSION QUANTITATIVE LIGAND EXPRESSION QUANTITATIVE LIGAND EXPRESSION

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