Activating natural cytotoxicity receptors of natural killer cells in cancer and infection

Koch, Joachim; Steinle, Alexander; Watzl, Carsten; Mandelboim, Ofer

doi:10.1016/j.it.2013.01.003

Cited by 276 publications

(302 citation statements)

References 107 publications

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“…Natural cytotoxicity receptors (NCRs) on natural killer (NK) cells include the NKp30 (also known as NCR3) and NKp46 receptors that signal through the immunoreceptor tyrosine-based activation motif (ITAM)-bearing CD3ζ or high-affinity IgE receptor subunit-γ (FcεRIγ) adaptor proteins and NKp44 (also known as NCR2) that signals using the ITAM-bearing DAP12 adaptor protein (also known as TYROBP) 87 . The activating CD94-NKG2C (natural killer group 2, member C) receptor that recognizes HLA-E and many of the activating killer cell immunoglobulin-like receptors (KIRs) also use DAP12 (REF.…”

Section: Box 2 | Regulation Of Nk Cells By Activating and Inhibitory mentioning

confidence: 99%

Natural killer cell memory in infection, inflammation and cancer

2016

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| Immunological memory can be defined as a quantitatively and qualitatively enhanced immune response upon rechallenge. For natural killer (NK) cells, two main types of memory exist. First, similarly to T cells and B cells, NK cells can exert immunological memory after encounters with stimuli such as haptens or viruses, resulting in the generation of antigen-specific memory NK cells. Second, NK cells can remember inflammatory cytokine milieus that imprint long-lasting non-antigen-specific NK cell effector function. The basic concepts derived from studying NK cell memory provide new insights about innate immunity and could lead to novel strategies to improve treatments for infectious diseases and cancer.

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Section: Box 2 | Regulation Of Nk Cells By Activating and Inhibitory mentioning

confidence: 99%

Natural killer cell memory in infection, inflammation and cancer

2016

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“…For example, the Natural Cytotoxicity Receptors (NCRs) NKp46, NKp30, and NKp44, play an important role in human NK cell-mediated recognition and killing of virally infected and tumor cells, and also induce the release of a number of cytokines and chemotactic factors. 10,12 In addition, NKp30 and NKp46 mediate regulatory interactions occurring between NK and different leukocytes, including dendritic cells (DCs), neutrophils, eosinophils, macrophages, and T cells. 5-9 NCRs were identified and molecularly characterized in ‘90s.…”

Section: Introductionmentioning

confidence: 99%

“…16-21 In spite of many efforts, so far, the panel of the NCR ligands has been only partially defined. 10,12,22 A reason of these difficulties is related to the fact that study models of receptor-ligand interaction for the NCR are rather limited, as only NKp46 is expressed also on NK cells of rat and mouse. Moreover, although the NCRs belong to the Ig superfamily, they greatly differ in their molecular structure, implying that their ligands may be rather heterogeneous.…”

Section: Introductionmentioning

confidence: 99%

Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor

et al. 2018

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The release of soluble ligands of activating Natural Killer (NK) cell receptors may represent a regulatory mechanism of NK cell function both in physiologic and in pathologic conditions. Here, we identified the extracellular matrix protein Nidogen-1 (NID1) as a ligand of NKp44, an important activating receptor expressed by activated NK cells. When released as soluble molecule, NID1 regulates NK cell function by modulating NKp44-induced IFN-γ production or cytotoxicity. In particular, it also modulates IFN-γ production induced by Platelet-Derived Growth Factor (PDGF)-DD following NKp44 engagement. We also show that NID1 may be present at the cell surface. In this form or when bound to a solid support (bNID1), NID1 fails to induce NK cell cytotoxicity or cytokine release. However, analysis by mass spectrometry revealed that exposure to bNID1 can induce in human NK cells relevant changes in the proteomic profiles suggesting an effect on different biological processes.

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“…NKp46 is an important receptor in NK lytic function in infection and cancer, known to recognize several virus-specific ligands in virus-infected cells. 56–58 Currently, its ligand(s) in cancer cells remains to be identified. 58 Thus it is possible that its decreased expression in NK cells upon entinostat exposure does not impact NK lysis of the tumor cell lines used in our study or is overcome by the overall observed increase in other activating ligands and effector molecules.…”

Section: Discussionmentioning

confidence: 99%

“…56–58 Currently, its ligand(s) in cancer cells remains to be identified. 58 Thus it is possible that its decreased expression in NK cells upon entinostat exposure does not impact NK lysis of the tumor cell lines used in our study or is overcome by the overall observed increase in other activating ligands and effector molecules. Entinostat also induced activation of CD56 BRIGHT immature NK cells from healthy donors and cancer patients (Figures 6 and 7).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

et al. 2018

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Checkpoint inhibitors targeting the PD-1/PD-L1 axis are promising immunotherapies shown to elicit objective responses against multiple tumor types, yet these agents fail to benefit most patients with carcinomas. This highlights the need to develop effective therapeutic strategies to increase responses to PD-1/PD-L1 blockade. Histone deacetylase (HDAC) inhibitors in combination with immunotherapies have provided preliminary evidence of anti-tumor effects. We investigated here whether exposure of either natural killer (NK) cells and/or tumor cells to two different classes of HDAC inhibitors would augment (a) NK cell‒mediated direct tumor cell killing and/or (b) antibody-dependent cellular cytotoxicity (ADCC) using avelumab, a fully human IgG1 monoclonal antibody targeting PD-L1. Treatment of a diverse array of human carcinoma cells with a clinically relevant dose of either the pan-HDAC inhibitor vorinostat or the class I HDAC inhibitor entinostat significantly enhanced the expression of multiple NK ligands and death receptors resulting in enhanced NK cell‒mediated lysis. Moreover, HDAC inhibition enhanced tumor cell PD-L1 expression both in vitro and in carcinoma xenografts. These data demonstrate that treatment of a diverse array of carcinoma cells with two different classes of HDAC inhibitors results in enhanced NK cell tumor cell lysis and avelumab-mediated ADCC. Furthermore, entinostat treatment of NK cells from healthy donors and PBMCs from cancer patients induced an activated NK cell phenotype, and heightened direct and ADCC-mediated healthy donor NK lysis of multiple carcinoma types. This study thus extends the mechanism and provides a rationale for combining HDAC inhibitors with PD-1/PD-L1 checkpoint blockade to increase patient responses to anti-PD-1/PD-L1 therapies.

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Activating natural cytotoxicity receptors of natural killer cells in cancer and infection

Cited by 276 publications

References 107 publications

Natural killer cell memory in infection, inflammation and cancer

Natural killer cell memory in infection, inflammation and cancer

Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

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