Identification of an ADAM17 Cleavage Region in Human CD16 (FcγRIII) and the Engineering of a Non-Cleavable Version of the Receptor in NK Cells

Jing, Yawu; Ni, Zhenya; Wu, Jianming; Higgins, Lee Ann; Markowski, Todd W.; Kaufman, Dan S.; Walcheck, Bruce

doi:10.1371/journal.pone.0121788

Cited by 114 publications

(153 citation statements)

References 56 publications

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“…Others subsequently showed that CD16A release by NK cells was mediated by a metalloprotease . Both allelic variants of CD16A undergo this cleavage process upon NK cell activation . There has been some controversy, however, in the proteolytic mechanism involved.…”

Section: Regulation Of Cd16a Surface Density By Adam17mentioning

confidence: 99%

“…Some studies have suggested the role of matrix metalloproteinases (MMPs), such as membrane‐type 6 MMP . More recently, several studies have shown that highly selective inhibitors of ADAM17, also referred to as TNF‐α converting enzyme (TACE), block CD16A cleavage upon NK cell activation by various means . Moreover, Tsukerman et al.…”

Section: Regulation Of Cd16a Surface Density By Adam17mentioning

confidence: 99%

“…ADAM17 is constitutively expressed on the surface of NK cells, and it cleaves its substrates typically in a cis manner at an extracellular location proximal to the cell membrane . A single cleavage site has been identified in CD16A released from activated human NK cells, located between alanine‐195 and valine‐196 (Fig. ).…”

Section: Regulation Of Cd16a Surface Density By Adam17mentioning

confidence: 99%

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Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

Mishra

Walcheck

2019

Journal of Leukocyte Biology

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Human NK cell antitumor activities involve Ab‐dependent cell‐mediated cytotoxicity (ADCC), which is a key mechanism of action for several clinically successful tumor‐targeting therapeutic mAbs. Human NK cells exclusively recognize these Abs by the Fcγ receptor CD16A (FcγRIIIA), one of their most potent activating receptors. Unlike other activating receptors on NK cells, CD16A undergoes a rapid down‐regulation in expression by a proteolytic process following NK cell activation with various stimuli. In this review, the role of a disintegrin and metalloproteinase‐17 (ADAM17) in CD16A cleavage and as a regulatory checkpoint is discussed. Several studies have examined the effects of inhibiting ADAM17 or CD16A cleavage directly during NK cell engagement of Ab‐coated tumor cells, which resulted in strengthened Ab tethering, decreased tumor cell detachment, and enhanced CD16A signaling and cytokine production. However, the effects of either manipulation on ADCC have varied between studies, which may be due to dissimilar assays and the contribution of different killing processes by NK cells. Of importance is that NK cells under various circumstances, including in the tumor microenvironment of patients, down‐regulate CD16A and this appears to impair their function. Considerable progress has been made in the development of ADAM17 inhibitors, including human mAbs that have advantages of high specificity and increased half‐life in vivo. These inhibitors may provide a therapeutic means of increasing ADCC potency and/or antitumor cytokine production by NK cells in an immunosuppressive tumor microenvironment, and if used in combination with tumor‐targeting Abs or NK cell‐based adoptive immunotherapies may improve their efficacy.

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Section: Regulation Of Cd16a Surface Density By Adam17mentioning

confidence: 99%

Section: Regulation Of Cd16a Surface Density By Adam17mentioning

confidence: 99%

Section: Regulation Of Cd16a Surface Density By Adam17mentioning

confidence: 99%

See 1 more Smart Citation

Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

Mishra

Walcheck

2019

Journal of Leukocyte Biology

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“…Another method to inhibit the cleavage of CD16 is a genetic modification. The substitution of the serine residue at position 197 in CD16 by a proline prevents the cleavage of CD16 on NK cells [104]. It may be possible to promote the antitumor effect by using a CD16 mutant.…”

Section: Synergistic Effect: Antibody Drugsmentioning

confidence: 99%

Clinical Applications of Natural Killer Cells

Harada¹,

Teraishi²,

Ishii³

et al. 2017

Natural Killer Cells

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Natural killer (NK) cells are an essential component of the innate immune system, and they play a crucial role in immunity against malignancies. Recent advances in our understanding of NK cell biology have paved the way for new therapeutic strategies based on NK cells for the treatment of various cancers. In this section, we will focus on NK cell immunotherapy, including the enhancement of antibody-dependent cellular cytotoxicity, the manipulation of receptor-mediated activation, inclusion criteria based on killer cell immunoglobulin-like receptor (KIR) ligand mismatches, and adoptive immunotherapy with ex vivo expanded chimeric antigen receptor (CAR)-engineered or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack any recipient tissues based on allogeneic human leukocyte antigens (HLAs), suggesting that NK-mediated antitumor effects may be achieved without the risk of graft-versus-host disease (GvHD). Despite reports of clinical efficacy, the application of NK cell immunotherapy is limited. Developing strategies for manipulating NK cell products, host factors, and tumor targets are thus current subjects of diligent study. Research into the biology of NK cells has indicated that NK cell immunotherapy has the potential to become the forefront of cancer immunotherapy in the coming years.

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“…In addition, mouse CD16 was shown not to be cleaved by ADAM17 [7] . Furthermore, when a single amino acid in the RESEARCH HIGHLIGHT human CD16 is replaced by the corresponding amino acid in mice, the majority of the cleavage is lost [8] .…”

Section: Introductionmentioning

confidence: 99%

A double-edged sword - the role of human ADAM17 in NK cell activity

Schmiedel

Mandelboim

Tsukerman³

2017

Can Cell Microenviron

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ADAM17 is a pleiotropic sheddase that regulates the activity of diverse membrane-anchored proteins by proteolytic cleavage. Also, many immune functions depend on ADAM17 activity, for instance CD16 and TNFα, two key effector molecules of Natural Killer cells, are cleaved by this enzyme. Whereas CD16 is shed from the surface and therefore its activity is terminated by ADAM17, TNFα requires shedding to be soluble and fulfil its effector functions. Due to these antagonistic effects on immune system activity, clinical benefits of ADAM17 inhibition for the treatment of cancer patients are hard to predict. Recently, we reported of a patient with a very rare genetic deficiency of ADAM17 leading to a complete loss of ADAM17 protein. We characterized the patient's PBMCs for cytokine secretion in response to LPS stimulation, as well as for antibody-dependent cellular cytotoxicity (ADCC) effector functions and IFNγ release following engagement of CD16. In this short review, we highlight these recent findings and discuss putative consequences for the clinical use of inhibitors for ADAM17.Keywords: ADAM17 deficiency; Marimastat; NK cells; CD16; ADCC To cite this article: Dominik Schmiedel, et al. A double-edged sword -the role of human ADAM17 in NK cell activity. Can

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Identification of an ADAM17 Cleavage Region in Human CD16 (FcγRIII) and the Engineering of a Non-Cleavable Version of the Receptor in NK Cells

Cited by 114 publications

References 56 publications

Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

Clinical Applications of Natural Killer Cells

A double-edged sword - the role of human ADAM17 in NK cell activity

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