A Radioactive-Free Method for the Thorough Analysis of the Kinetics of Cell Cytotoxicity

The cytotoxic activity of T cells and Natural Killer cells is usually measured with the chromium release assay (CRA), which involves the use of 51Chromium (51Cr), a radioactive substance dangerous to the operator and expensive to handle and dismiss. The accuracy of the measurements depends on how well the target cells incorporate 51Cr during labelling which, in turn, depends on cellular division. Due to bystander metabolism, the target cells spontaneously release 51Cr, producing a high background noise. Alternative radioactive-free methods have been developed. Here, we compare a bioluminescence (BLI)-based and a carboxyfluorescein succinimidyl ester (CFSE)-based cytotoxicity assay to the standard radioactive CRA. In the first assay, the target cells stably express the enzyme luciferase, and vitality is measured by photon emission upon the addition of the substrate d-luciferin. In the second one, the target cells are labelled with CFSE, and the signal is detected by Flow Cytometry. We used these two protocols to measure cytotoxicity induced by treatment with NK cells. The cytotoxicity of NK cells was determined by adding increasing doses of human NK cells. The results obtained with the BLI method were consistent with those obtained with the CRA- or CFSE-based assays 4 hours after adding the NK cells. Most importantly, with the BLI assay, the kinetic of NK cells’ killing was thoroughly traced with multiple time point measurements, in contrast with the single time point measurement the other two methods allow, which unveiled additional information on NK cell killing pathways.

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Elevated CD56dimCD16neg NK Cells on Day 28 after HCT: Role in Immunity Against Viral Infections or Residual Tumor Cells?.

Blood ◽

10.1182/blood.v110.11.1977.1977 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1977-1977

Author(s):

Faisal Khan ◽

Jan Storek

Keyword(s):

Nk Cells ◽

Mononuclear Cells ◽

Viral Infections ◽

Nk Cell ◽

Cell Subset ◽

Lymphocyte Subset ◽

Target Cells ◽

Multiple Time ◽

Healthy Individuals ◽

Autologous Hct

Abstract Natural killer (NK) cells represent a lymphocyte subset important in the immune surveillance against virus infected and malignant cells. In humans, two major NK cell subsets have been defined by CD56 and CD16 staining: Regulatory NK cells (CD56 high CD16 neg), which are potent cytokine (IFNg) producers; and Cytolytic NK cells (CD56 dim CD16 pos) that are involved in target cell lysis. Functions of other NK cell subset are unknown. One of such subset, CD56 dimCD16 neg NK cells have recently been reported to represent cytolytic cells, degranulated after contact with target cells. NK cells are the first lymphocyte subset recovering to normal quantity and function after an allogeneic or autologous HCT, typically by 4 weeks post HCT. In the present investigation, we attempted to determine percentages of following NK cell subsets (Regulatory NK cells, Cytolytic NK cells, CD56dimCD16 neg, CD56 highCD16 pos and CD56neg CD16 high NK cells) at multiple time points (day 28, 56, 84, 180 and 365) after allogeneic (n= 32) and autologous (n= 25) HCT and compared with that of healthy individuals (n=14). Whole blood specimen was incubated with fluorochrome-conjugated monoclonal antibodies (CD3-ECD, CD14-PE, CD56-FITC and CD16-PC5) and analyzed by four color flowcytometry. NK cells were defined as mononuclear cells expressing CD16 or CD56 and not expressing CD3 or CD14. The most striking finding was that of significant increase in percentage of CD56dimCD16−ve cells (among NK cells) on day 28. This was true for both autologous HCT recipient (n=24; median = 1.02% of total NK cells) and allogeneic HCT recipient (n=26; median = 1.1% of total NK cells) in comparison to the healthy individuals (n=14; median = 0.56% of total NK cells). We speculate the rise in CD56dimCD16−ve NK cells at 1 month post HCT may be due to increased degranulation of cytolytic NK cells in response to viral infections or residual malignancy.

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Cord Blood NK Cytotoxic Activity Can Be Selelctively Modulated by Accessory.

Blood ◽

10.1182/blood.v110.11.3272.3272 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3272-3272

Author(s):

Dongxia Xing ◽

Sufang Li ◽

Robinson N. Simon ◽

Decker William ◽

Yang Hong ◽

...

Keyword(s):

Cord Blood ◽

Nk Cells ◽

Nk Cell ◽

Cytolytic Activity ◽

Chromium Release Assay ◽

Allogeneic Mscs ◽

Chromium Release ◽

Accessory Cells ◽

Selective Modulation ◽

Release Assay

Abstract Introduction The expansion of cord blood (CB) derived natural killer (NK) cells is a promising cell therapy approach. CB NK cell expansion and activation has proven to be feasible and effective. However, the selectivity of NK killing in an allograft setting raises concern. Accessory cells, in particular dendritic cells and mesenchymal stem cells (MSCs), have been shown to interact with and modulate NK cell proliferation and function. We explored the ability of accessory cells to modulate NK activity in the setting of clinically-relevant CB NK expansion protocols. Methods Human MSCs were isolated from normal bone marrow donors. 5 × 106 CD56-selected NK cells or 5 × 107 unselected or CD3-depleted CB mononuclear cells (MNC) (averaging 10% CD56+ NK cells) were layered on top of the MSCs in the presence of 200u/mL IL-2. CB NK cells were tested for cytolytic activity by 51Cr release assay using MSCs and K562 AML cells. IFN-g secretion was detected by Elispot assay. Results Cord blood-derived NK cells activated by exposure to IL-2 efficiently kill allogeneic MSCs in vitro. A 4 hour chromium release assay revealed that CD56-selected CB NK cells lysed 60% of allogeneic MSCs at E:T ratio 10:1. MSC co-culture with CB NK induced IFN-g secretion as determined by IFN-γ Elispot assay. In contrast, unselected or CD3-depleted CB MNCs with equal numbers of CD56+ NK cells were unable to lyse MSCs despite IL-2 activation. This suggests that CB accessory cells can modulate the activation or cytolytic activity of CB-derived NK cells. To address these two possibilities, we tested the ability of these CB cultures to kill a classic NK target, K562 human myeloid leukemia cells. Surprisingly, in all three CB cultures NK efficiently lysed K562 cells, 95% of lysis at 10:1 E:T ratio by chromium release assay suggesting that these accessory cells did not prevent IL-2 activation of NK cells, but selectively-modulated the cytolytic activity. Thus, preserving anti-leukemia killing while protecting non-malignant MSCs. Conclusions Our data provide evidence for selective modulation of cord blood-derived NK cell cytolytic activity by CB accessory cells. Indeed, activation of cord-derived NK cells in the presence on CD3-depleted accessory cells yields NK cells capable of killing K562 target cells but not allogeneic MSCs. Although the underlying mechanism is unknown, this selective modulation of NK cells may be exploited in the clinical expansion of cord blood NK cells.

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Cryopreservation impairs 3-D migration and cytotoxicity of natural killer cells

Nature Communications ◽

10.1038/s41467-020-19094-0 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Christoph Mark ◽

Tina Czerwinski ◽

Susanne Roessner ◽

Astrid Mainka ◽

Franziska Hörsch ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Solid Tumors ◽

Cell Function ◽

Nk Cell ◽

Safety Evaluation ◽

Collagen Gel ◽

Target Cells ◽

Effector Cells ◽

Chromium Release

Abstract Natural killer (NK) cells are important effector cells in the immune response to cancer. Clinical trials on adoptively transferred NK cells in patients with solid tumors, however, have thus far been unsuccessful. As NK cells need to pass stringent safety evaluation tests before clinical use, the cells are cryopreserved to bridge the necessary evaluation time. Standard degranulation and chromium release cytotoxicity assays confirm the ability of cryopreserved NK cells to kill target cells. Here, we report that tumor cells embedded in a 3-dimensional collagen gel, however, are killed by cryopreserved NK cells at a 5.6-fold lower rate compared to fresh NK cells. This difference is mainly caused by a 6-fold decrease in the fraction of motile NK cells after cryopreservation. These findings may explain the persistent failure of NK cell therapy in patients with solid tumors and highlight the crucial role of a 3-D environment for testing NK cell function.

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Sialic Acids and Their Influence on Human NK Cell Function

Cells ◽

10.3390/cells10020263 ◽

2021 ◽

Vol 10 (2) ◽

pp. 263

Author(s):

Philip Rosenstock ◽

Thomas Kaufmann

Keyword(s):

Nk Cells ◽

Immune Cells ◽

Cell Function ◽

Nk Cell ◽

Sialic Acids ◽

Innate Immune ◽

Target Cells ◽

Carbon Backbone ◽

Nk Cell Receptors ◽

Cell Inhibition

Sialic acids are sugars with a nine-carbon backbone, present on the surface of all cells in humans, including immune cells and their target cells, with various functions. Natural Killer (NK) cells are cells of the innate immune system, capable of killing virus-infected and tumor cells. Sialic acids can influence the interaction of NK cells with potential targets in several ways. Different NK cell receptors can bind sialic acids, leading to NK cell inhibition or activation. Moreover, NK cells have sialic acids on their surface, which can regulate receptor abundance and activity. This review is focused on how sialic acids on NK cells and their target cells are involved in NK cell function.

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Influenza A Virus Hemagglutinin and Other Pathogen Glycoprotein Interactions with NK Cell Natural Cytotoxicity Receptors NKp46, NKp44, and NKp30

Viruses ◽

10.3390/v13020156 ◽

2021 ◽

Vol 13 (2) ◽

pp. 156

Author(s):

Jasmina M. Luczo ◽

Sydney L. Ronzulli ◽

Stephen M. Tompkins

Keyword(s):

Influenza Virus ◽

Nk Cells ◽

Influenza A Virus ◽

Influenza A ◽

Nk Cell ◽

Influenza Virus Infection ◽

Target Cells ◽

Natural Cytotoxicity ◽

Activating Receptors ◽

Natural Cytotoxicity Receptors

Natural killer (NK) cells are part of the innate immunity repertoire, and function in the recognition and destruction of tumorigenic and pathogen-infected cells. Engagement of NK cell activating receptors can lead to functional activation of NK cells, resulting in lysis of target cells. NK cell activating receptors specific for non-major histocompatibility complex ligands are NKp46, NKp44, NKp30, NKG2D, and CD16 (also known as FcγRIII). The natural cytotoxicity receptors (NCRs), NKp46, NKp44, and NKp30, have been implicated in functional activation of NK cells following influenza virus infection via binding with influenza virus hemagglutinin (HA). In this review we describe NK cell and influenza A virus biology, and the interactions of influenza A virus HA and other pathogen lectins with NK cell natural cytotoxicity receptors (NCRs). We review concepts which intersect viral immunology, traditional virology and glycobiology to provide insights into the interactions between influenza virus HA and the NCRs. Furthermore, we provide expert opinion on future directions that would provide insights into currently unanswered questions.

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GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner

Cancers ◽

10.3390/cancers13081802 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1802

Author(s):

Nayoung Kim ◽

Mi Yeon Kim ◽

Woo Seon Choi ◽

Eunbi Yi ◽

Hyo Jung Lee ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Negative Regulator ◽

Target Cells ◽

Dependent Manner ◽

Cell Functions ◽

Cell Based Therapy ◽

Activating Receptors ◽

Gsk 3Β

Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.

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Soluble and Exosome-Bound α-Galactosylceramide Mediate Preferential Proliferation of Educated NK Cells with Increased Anti-Tumor Capacity

Cancers ◽

10.3390/cancers13020298 ◽

2021 ◽

Vol 13 (2) ◽

pp. 298

Author(s):

Arnika K. Wagner ◽

Ulf Gehrmann ◽

Stefanie Hiltbrunner ◽

Valentina Carannante ◽

Thuy T. Luu ◽

...

Keyword(s):

Nk Cells ◽

Cancer Immunotherapy ◽

Nk Cell ◽

Mouse Strains ◽

Target Cells ◽

Class I Mhc ◽

Mhc I ◽

Cell Responses ◽

Missing Self

Natural killer (NK) cells can kill target cells via the recognition of stress molecules and down-regulation of major histocompatibility complex class I (MHC-I). Some NK cells are educated to recognize and kill cells that have lost their MHC-I expression, e.g., tumor or virus-infected cells. A desired property of cancer immunotherapy is, therefore, to activate educated NK cells during anti-tumor responses in vivo. We here analyze NK cell responses to α-galactosylceramide (αGC), a potent activator of invariant NKT (iNKT) cells, or to exosomes loaded with αGC. In mouse strains which express different MHC-I alleles using an extended NK cell flow cytometry panel, we show that αGC induces a biased NK cell proliferation of educated NK cells. Importantly, iNKT cell-induced activation of NK cells selectively increased in vivo missing self-responses, leading to more effective rejection of tumor cells. Exosomes from antigen-presenting cells are attractive anti-cancer therapy tools as they may induce both innate and adaptive immune responses, thereby addressing the hurdle of tumor heterogeneity. Adding αGC to antigen-loaded dendritic-cell-derived exosomes also led to an increase in missing self-responses in addition to boosted T and B cell responses. This study manifests αGC as an attractive adjuvant in cancer immunotherapy, as it increases the functional capacity of educated NK cells and enhances the innate, missing self-based antitumor response.

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Immunosenescence of Natural Killer Cells, Inflammation, and Alzheimer’s Disease

International Journal of Alzheimer s Disease ◽

10.1155/2018/3128758 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Corona Solana ◽

Raquel Tarazona ◽

Rafael Solana

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Neurodegenerative Disorder ◽

The Elderly ◽

Lymphoid Cells ◽

Target Cells ◽

The Brain

Alzheimer’s disease (AD) represents the most common cause of dementia in the elderly. AD is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Although the aetiology of AD is not clear, both environmental factors and heritable predisposition may contribute to disease occurrence. In addition, inflammation and immune system alterations have been linked to AD. The prevailing hypothesis as cause of AD is the deposition in the brain of amyloid beta peptides (Aβ). Although Aβ have a role in defending the brain against infections, their accumulation promotes an inflammatory response mediated by microglia and astrocytes. The production of proinflammatory cytokines and other inflammatory mediators such as prostaglandins and complement factors favours the recruitment of peripheral immune cells further promoting neuroinflammation. Age-related inflammation and chronic infection with herpes virus such as cytomegalovirus may also contribute to inflammation in AD patients. Natural killer (NK) cells are innate lymphoid cells involved in host defence against viral infections and tumours. Once activated NK cells secrete cytokines such as IFN-γ and TNF-α and chemokines and exert cytotoxic activity against target cells. In the elderly, changes in NK cell compartment have been described which may contribute to the lower capacity of elderly individuals to respond to pathogens and tumours. Recently, the role of NK cells in the immunopathogenesis of AD is discussed. Although in AD patients the frequency of NK cells is not affected, a high NK cell response to cytokines has been described together with NK cell dysregulation of signalling pathways which is in part involved in this altered behaviour.

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151 Potentiating the Large-Scale Expansion and Engineering of Peripheral Blood-Derived CAR NK Cells for Off-the-Shelf Application

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.151 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A159-A159

Author(s):

Michael Whang ◽

Ming-Hong Xie ◽

Kate Jamboretz ◽

Hadia Lemar ◽

Chao Guo ◽

...

Keyword(s):

T Cells ◽

Cell Therapy ◽

Nk Cells ◽

Peripheral Blood ◽

Nk Cell ◽

Adoptive Cell Therapy ◽

Therapeutic Window ◽

Target Cells ◽

Healthy Donors ◽

Custom Made

BackgroundPeripheral blood natural killer (NK) cells are mature cytotoxic innate lymphocytes possessing an inherent capacity for tumor cell killing, thus making them attractive candidates for adoptive cell therapy. These NK cells are also amenable to CRISPR and chimeric antigen receptor (CAR) genomic engineering for enhanced functions. Moreover, NK cells possess an inherent capacity for off-the-shelf therapy since they are not known to cause graft-versus-host disease, unlike T cells. Presently, approved CAR cell therapy is custom-made from each patient‘s own T cells, a process that can limit patient pool, narrow therapeutic window, and contribute to product variability. In this study, we investigate whether peripheral blood NK cells from a selected donor can be edited, engineered, and expanded sufficiently for off-the-shelf use in a wide patient population.MethodsUsing the CRISPR/Cas9 system, we knocked out CISH expression in isolated peripheral blood NK cells from 3 healthy donors. Subsequently, we expanded edited NK cells by using IL-2 and sequential stimulations using NKSTIM, a modified K562 stimulatory cell line expressing membrane-bound form of IL-15 (mbIL-15) and 4-1BBL. IL-12 and IL-18 were added twice during expansion to drive memory-like NK cell differentiation. We transduced the expanded NK cells to express engineered CD19-targeted CAR and mbIL-15 during an interval between the first and second NKSTIM pulses. We assessed NK cell cytotoxicity against Nalm6 target cells by IncuCyte.ResultsIsolated peripheral blood NK cells from 3 healthy donors were successfully edited using CRISPR/Cas9, engineered to express high levels of CAR, extensively expanded using a series of NKSTIM pulses in the presence of IL-2, and differentiated into memory-like NK cells using IL-12 and IL-18. Interestingly, NK cells from the 3 donors exhibited distinct outcomes. NK cells from one donor reached a peak expansion limit of approximately 7-million-fold before undergoing contraction whereas NK cells from two donors continued to expand over the length of the study surpassing 100-million-fold expansion, without appearing to have reached a terminal expansion limit. At the end of the study, NK cells from one donor exceeded 1-billion-fold expansion and maintained 88% cytolytic activity compared to Nkarta’s standard process control in a 72-hour IncuCyte assay.ConclusionsIn this study, we demonstrate that healthy donor-derived peripheral blood NK cells are capable of expanding over billion-fold while maintaining potency. These results provide a rationale for the development of off-the-shelf CAR NK cell therapies using NK cells from donors selected to provide optimal product characteristics.Ethics ApprovalHuman samples were collected with written informed consent by an approved vendor.

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894 The bispecific innate cell engagers AFM13 (CD30/CD16A) and AFM24 (EGFR/CD16A) increase the fraction of tumor target-responsive NK cells and boost serial killing

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.894 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A938-A938

Author(s):

Chiara Zambarda ◽

Karolin Guldevall ◽

Chiara Zambarda ◽

Karolin Guldevall ◽

Christian Breunig ◽

...

Keyword(s):

Nk Cells ◽

Single Cell ◽

Tumor Cells ◽

Cell Biology ◽

Nk Cell ◽

Biological Evaluation ◽

Target Cells ◽

List Type ◽

Tumor Target ◽

Serial Killing

BackgroundThe use of bispecific natural killer (NK) cell engagers has emerged as a successful strategy for immune cell activation and killing of tumor cells through antibody-dependent cellular cytotoxicity (ADCC). Among these, tetravalent, bispecific innate cell engagers (ICE®) with specificity for the activating receptor CD16A selectively triggering innate responses from NK cells or macrophages represent the most clinically advanced concept. The CD30/CD16A specific ICE® AFM13, has shown efficacy in patients with CD30+ lymphomas as monotherapy1 and combination therapy with check-point inhibitors2 and most recently in combination with adoptive NK cell therapy.3 The EGFR/CD16A specific ICE® AFM24, targeting a variety of solid tumors like colorectal, or lung cancer with a unique mode of action independent of EGFR signaling inhibition, is currently evaluated in an ongoing Ph1/2a clinical study.MethodsWe used a microchip-based screening with single cell resolution4 to elucidate the dynamic responses of individual NK cells towards tumor target cells upon treatment with AFM13 or AFM24.ResultsWe found that AFM13 and AFM24 mediated potent activation of NK cells, leading to increased responsive cytotoxic NK cells and significantly increased the number of NK cells that exerted engagement with multiple target cells rendering these NK cells serial killers. Strikingly, bispecific ICE® molecules triggered stronger cytotoxic responses compared to monoclonal antibodies. One suggested strategy to boost killing by NK cells is to use molecular inhibitors or protein constructs that prevent shedding of CD16.5 However, previous results have shown that this can lead to impaired detachment from target cells, reducing the capacity for an individual NK cell to form serial contacts to target cells.6 We observed that the elevated NK cell killing induced by ICE® molecules was largely conserved when cells were treated with the shedding inhibitor Batimastat. Analysis of the functional dynamics of NK cells revealed that inhibition of CD16 shedding prevented NK cell detachment from target cells, resulting in cell cluster formation. This might strongly impact targeting of distant tumor cells by an individual NK cell thus limiting its anti-tumoral activity.ConclusionsIn conclusion, we show that both AFM13 and AFM24 increase the fraction of tumor-target responsive NK cells and boost serial killing of target cells by individual NK cells. Based on these data, ICE® molecules can be characterized as potent anti-tumoral agents leveraging the enormous potential of NK cells while maintaining crucial features of NK cell biology.AcknowledgementsWe thank members of the Önfelt lab for their valuable help and feedback.ReferencesSawas A, Elgedawe H, Vlad G, Lipschitz M, Chen P-H, Rodig SJ, et al. Clinical and biological evaluation of the novel CD30/CD16A tetravalent bispecific antibody (AFM13) in relapsed or refractory CD30-positive lymphoma with cutaneous presentation: a biomarker phase Ib/IIa study (NCT03192202). Blood 2018;132(Supplement 1):2908–2908.Bartlett NL, Herrera AF, Domingo-Domenech E, Mehta A, Forero-Torres A, Garcia-Sanz R, et al. A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 2020. Blood 2020;136(21):2401–2409.Kerbauy LN, Marin ND, Kaplan M, Banerjee PP, Berrien-Elliott MM, Becker-Hapak M, et al. Combining AFM13, a bispecific CD30/CD16 antibody, with cytokine-activated blood and cord blood–derived NK cells facilitates CAR-like responses against CD30 + malignancies. Clin Cancer Res Epub 2021.Guldevall K, Brandt L, Forslund E, Olofsson K, Frisk TW, Olofsson PE, et al. Microchip screening platform for single cell assessment of NK cell cytotoxicity. Front Immunol 2016;7:119.Romee R, Foley B, Lenvik T, Wang Y, Zhang B, Ankarlo D, et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 2013;121(18):3599–608.Srpan K, Ambrose A, Karampatzakis A, Saeed M, Cartwright ANR, Guldevall K, et al. Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells. J Cell Biol 2018;217(9):3267–83.Ethics ApprovalThis work was performed with NK cells from healthy anonymous blood donors, which requires no ethical permit according to local regulations.

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