Natural Killer Cells: Biology, Physiology and Medicine – Part 1

Bryceson, Yenan T.; Ljunggren, Hans‐Gustaf

doi:10.1159/000325332

Cited by 9 publications

(12 citation statements)

References 39 publications

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“…12, 13 Genetic immunodeficiencies resulting in NK cell defects are also associated with malignancies, presumably because NK cells are held to serve an important role in tumor surveillance. 14, 15 Aside from the occurrence of recalcitrant viral infections, DOCK8-deficient patients also have susceptibility to cancers, which in this case has been hypothesized to be linked to viral infections. 23 …”

Section: Discussionmentioning

confidence: 99%

Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency

Mizesko

Banerjee

Monaco-Shawver

et al. 2013

Journal of Allergy and Clinical Immunology

117

103

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Introduction DOCK8 mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, elevated IgE, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein (WASp) for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse (IS). DOCK8 activates Cdc42, which, together with WASp, coordinates F-actin reorganization. While abnormalities in T and B cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. Objectives Understand the role of DOCK8 in NK cell function in order to determine if NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. Methods A cohort of DOCK8-deficient patients was assembled and patient NK cells as well as NK cell lines with stably reduced DOCK8 expression were studied. NK cell cytotoxicity, F-actin content, and lytic immunological synapse formation were measured. Results DOCK8-deficient patient NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunological synapse without affecting overall NK cell F-actin content. Conclusions DOCK8 deficiency results in severely impaired NK cell function owing to an inability to form a mature lytic IS via targeted synaptic F-actin accumulation. This defect may underlie and explain important attributes of the DOCK8 deficiency clinical syndrome including the unusual susceptibility to viral infection and malignancy.

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Section: Discussionmentioning

confidence: 99%

Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency

Mizesko

Banerjee

Monaco-Shawver

et al. 2013

Journal of Allergy and Clinical Immunology

117

103

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“…Natural killer (NK) cells are immune cells that can eliminate cancer cells upon cell contact (1)(2)(3). NK cells express a repertoire of stimulatory receptors that mediate the release of cytotoxic chemicals when stimulated by antibodies or by cells that express stimulatory ligands.…”

Section: Introductionmentioning

confidence: 99%

“…Given that cancer cell killing is initiated via activation of NK cell stimulatory receptors, it is important to understand how the signal propagates and activates the downstream species that contribute to NK cell activation. Therefore, researchers (1)(2)(3)(4)6,7) have studied NK cell signaling and reported which species are activated downstream of the stimulatory receptors. Such findings are crucial in understanding how NK cell activation proceeds on the molecular level.…”

Section: Introductionmentioning

confidence: 99%

Enhancing network activation in Natural Killer cells: Predictions from in silico modeling

Makaryan

Finley

2018

Preprint

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Natural killer (NK) cells are innate immune effector cells that play an immediate role in host defense. NK cells contain a variety of stimulatory pathways that induce the release of cytotoxic chemicals when activated. Mathematical modeling of such pathways can inform us about the magnitude and kinetics of activation. This, in turn, can provide insight for NK cell-based therapies. To quantitatively understand the differences between three main stimulatory pathways in NK cells (CD16, 2B4 and NKG2D), we developed a mathematical model that mechanistically describes their intracellular signaling dynamics. In particular, the model predicts the dynamics of the phosphorylated receptors, pSFK, pErk, pAkt and pPLC , as these species contribute to cell activation. The model was fit to published experimental data and validated with separate experimental measurements. Modeling simulations show that the CD16 pathway exhibits rapid activation kinetics for all species, and co-stimulation of CD16 with either NKG2D or 2B4 induces the greatest magnitude of activation. Moreover, the magnitude of cell activation under co-stimulation is more sensitive to CD16 stimulation than either 2B4 or NKG2D stimulation. Overall, the model predicts CD16 stimulation is more influential in cell activation. These modeling results complement ongoing experimental work that applies CD16 stimulation for therapeutic purposes. IntroductionMathematical modeling of signal transduction pathways provides a framework that enables better cell engineering approaches. Indeed, many models have augmented our understanding of biological processes (Bellouquid and CH-Chaoui, 2014; Eftimie et al., 2016; Pappalardo et al., 2012) by generating quantitative detail and actionable insight. As an example, researchers investigating the EGFR pathway in an in silico cancer cell model demonstrated that inhibition of multiple upstream processes significantly attenuates signal propagation (Araujo et al., 2005). These findings would later support the use of multi-kinase inhibitors as a potential cancer therapeutic (Gridelli et al., 2007;Zhou, 2012). Despite such advances, a few areas of biology provide new opportunities to be explored by quantitative, engineering-based computational models (Baxter and Hodgkin, 2002). Immunology is one example, and in particular, tumor immunology can benefit from robust computational modeling. Recently, the advent of cancer immunotherapy (Bollino and Webb, 2017; Klingemann, 2005) has engendered a new hope for cancer patients and their families. In fact, immunotherapy is meritoriously considered a breakthrough therapeutic approach in the clinic, especially as an effective treatment for hematological cancers (Gattinoni et al., 2006; Mellman et al., 2011;Rosenberg et al., 2004). Ongoing work is aimed at achieving similar success for solid tumors. Mechanistic models of tumor-immune cell interactions can help identify new strategies and potentially enhance the success rate of immunotherapies against solid tumors.

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“…Among those therapies, NK cells have gained considerable interests. NK cells are known for their natural ability to lyse tumor cells in vitro without the need for prior sensitization 4 . They are the major cytotoxic effector cells of the innate immune system, constituting 5–15% of mature lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Adoptive natural killer cell therapy is effective in reducing pulmonary metastasis of Ewing sarcoma

et al. 2017

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The survival of patients with metastatic or relapsed Ewing sarcoma (ES) remains dismal despite intensification of combination chemotherapy and radiotherapy, precipitating the need for novel alternative therapies with minimal side effects. Natural killer (NK) cells are promising additions to the field of cellular immunotherapy. Adoptive NK cell therapy has shown encouraging results in hematological malignancies. Despite these initial promising successes, however, NK cell therapy for solid tumors remains to be investigated using in vivo tumor models. The purpose of this study is to evaluate the efficacy of ex vivo expanded human NK cells in controlling primary and metastatic ES tumor growth in vitro and in vivo. Using membrane-bound IL-21 containing K562 (K562-mbIL-21) expansion platform, we were able to obtain sufficient numbers of expanded NK (eNK) cells that display favorable activation phenotypes and inflammatory cytokine secretion, along with a strong in vitro cytotoxic effect against ES. Furthermore, eNK therapy significantly decreased lung metastasis without any significant therapeutic effect in limiting primary tumor growth in an in vivo xenograft model. Our data demonstrate that eNK may be effective against pulmonary metastatic ES, but challenges remain to direct proper trafficking and augmenting the cytotoxic function of eNK to target primary tumor sites.

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Natural Killer Cells: Biology, Physiology and Medicine – Part 1

Cited by 9 publications

References 39 publications

Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency

Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency

Enhancing network activation in Natural Killer cells: Predictions from in silico modeling

Adoptive natural killer cell therapy is effective in reducing pulmonary metastasis of Ewing sarcoma

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