scholarly journals Immunomodulatory Role of NK Cells during Antiviral Antibody Therapy

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 137
Author(s):  
Mar Naranjo-Gomez ◽  
Marine Cahen ◽  
Jennifer Lambour ◽  
Myriam Boyer-Clavel ◽  
Mireia Pelegrin
Keyword(s):  
B Cell ◽  
Nk Cells ◽  
Protective Immunity ◽  
Viral Infections ◽  
Nk Cell ◽  
Antibody Therapy ◽  
Cell Depletion ◽  
Immunomodulatory Activity ◽  
Cell Functions

Monoclonal antibodies (mAbs) are now considered as a therapeutic approach to prevent and treat severe viral infections. Using a mouse retroviral model, we showed that mAbs induce protective immunity (vaccinal effects). Here, we investigated the role of natural killer (NK) cells on this effect. NK cells are effector cells that are crucial to control viral propagation upon mAb treatment. However, their immunomodulatory activity during antiviral mAb immunotherapies has been little studied. Our data reveal that the mAb treatment of infected mice preserves the functional activation of NK cells. Importantly, functional NK cells play an essential role in preventing immune dysfunction and inducing antiviral protective immunity upon mAb therapy. Thus, NK cell depletion in mAb-treated, viral-infected mice leads to the upregulation of molecules involved in immunosuppressive pathways (i.e., PD-1, PD-L1 and CD39) on dendritic cells and T cells. NK cell depletion also abrogates the vaccinal effects induced by mAb therapy. Our data also reveal a role for IFNγ-producing NK cells in the enhancement of the B-cell responses through the potentiation of the B-cell helper properties of neutrophils. These findings suggest that preserved NK cell functions and counts might be required for achieving mAb-induced protective immunity. They open new prospects for improving antiviral immunotherapies.

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

Cancers ◽  
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.

scholarly journals Dysregulation of Natural Killer Cells in Obesity

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 573 ◽  
Author(s):  
Donal O’Shea ◽  
Andrew E. Hogan
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Viral Infections ◽  
Nk Cell ◽  
Viral Immunity ◽  
Host Protection ◽  
Cell Functions ◽  
Innate Lymphocytes ◽  
The Impact

Natural killer (NK) cells are a population of lymphocytes which classically form part of the innate immune system. They are defined as innate lymphocytes, due to their ability to kill infected or transformed cells without prior activation. In addition to their cytotoxic abilities, NK cells are also rapid producers of inflammatory cytokines such as interferon gamma (IFN-γ) and are therefore a critical component of early immune responses. Due to these unique abilities, NK cells are a very important component of host protection, especially anti-tumour and anti-viral immunity. Obesity is a worldwide epidemic, with over 600 million adults and 124 million children now classified as obese. It is well established that individuals who are obese are at a higher risk of many acute and chronic conditions, including cancer and viral infections. Over the past 10 years, many studies have investigated the impact of obesity on NK cell biology, detailing systemic dysregulation of NK cell functions. More recently, several studies have investigated the role of NK cells in the homeostasis of adipose tissue and the pathophysiology of obesity. In this review, we will discuss in detail these studies and focus on emerging data detailing the metabolic mechanisms altering NK cells in obesity.

Potential Role of NK Cells in the Induction of Immune Responses: Implications for NK Cell–Based Immunotherapy for Cancers and Viral Infections

2008 ◽  
Vol 27 (3) ◽  
pp. 93-110 ◽  
Author(s):  
Hiroshi Terunuma ◽  
Xuewen Deng ◽  
Zahidunnabi Dewan ◽  
Shigeyoshi Fujimoto ◽  
Naoki Yamamoto
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Potential Role ◽  
Viral Infections ◽  
Nk Cell

scholarly journals Role of KIR Receptor in NK Regulation during Viral Infections

Immuno ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 305-331
Author(s):  
Sabrina Rizzo ◽  
Giovanna Schiuma ◽  
Silvia Beltrami ◽  
Valentina Gentili ◽  
Roberta Rizzo ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Cell Activation ◽  
Viral Infections ◽  
Nk Cell ◽  
Human Leukocyte ◽  
Target Cells ◽  
Inhibitory Receptors ◽  
Receptor Repertoire

Natural Killer (NK) cells are key effectors of the innate immune system which represent the first line of defense against viral infections. NK cell activation depends on the engagement of a complex receptor repertoire expressed on their surface, consisting of both activating and inhibitory receptors. Among the known NK cell receptors, the family of killer Ig-like receptors (KIRs) consists in activating/inhibitory receptors that interact with specific human leukocyte antigen (HLA) molecules expressed on target cells. In particular, the expression of peculiar KIRs have been reported to be associated to viral infection susceptibility. Interestingly, a significant association between the development and onset of different human pathologies, such as tumors, neurodegeneration and infertility, and a clonal KIRs expression on NK cells has been described in presence of viral infections, supporting the crucial role of KIRs in defining the effect of viral infections in different tissues and organs. This review aims to report the state of art about the role of KIRs receptors in NK cell activation and viral infection control.

The Role of the PI3K-AKT-mTOR Pathway in NK Cell Anti-Tumor Reactivity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3690-3690
Author(s):  
Matthias Krusch ◽  
Julia Salih ◽  
Ingrid Kumbier ◽  
Carolin Fenner ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nk Cells ◽  
Signaling Pathways ◽  
Nk Cell ◽  
Mtor Pathway ◽  
Target Cells ◽  
Cellular Cytotoxicity ◽  
Cell Functions ◽  
Ifn Γ

Abstract Abstract 3690 Poster Board III-626 The phosphatidylinositol 3-kinase – protein kinase B – mammalian target of rapamycin (PI3K – AKT – mTOR) pathway was found to be abnormally activated in many malignancies. Thus, protein kinase (PK) inhibitors (PKI) targeting different signaling molecules of this pathway are presently under clinical evaluation e.g. in sarcoma, multiple myeloma, or renal cell cancer. However, PK are also responsible for most of the signal transduction in immune effector cells and control various effector mechanisms including proliferation, cellular cytotoxicity, and cytokine release. Among those immunoregulatory signaling pathways, the PI3K – AKT – mTOR pathway was found to play a central role in TLR-mediated release of cytokines in macrophages and DC as well as in the regulation of T cell functions. Little is known about the role of this pathway in NK cell-mediated anti-tumor reactivity. Here we analyzed the tumor cell-induced activation of PI3K, AKT, and mTOR in NK cells and the consequences of an inhibition of these molecules by therapeutic PKI for NK cell anti-tumor reactivity. We found that, in response to tumor target cells, PI3K, AKT, and mTOR are consecutively activated in NK cells as revealed by western blot analyses using phospho-specific antibodies. Presence of the specific PI3K-inhbitor BKM-120 concentration-dependently inhibited cytotoxicity and IFN-g production of NK cells, which is in line with available data defining PI3K as a central regulator of NK cell target recognition. The mTOR inhibitors Sirolimus, Temsirolimus, and Everolimus did not alter cytotoxicity but significantly impaired NK cell IFN-γ production. In contrast, Triciribine, a compound which inhibits the phosphorylation and thus activation of AKT, did not influence cytotoxicity and, tantalizingly, even enhanced NK cell IFN-γ production. Thus, after target cell recognition and the activation of proximal PK like PI3K, different and at least partially independent signaling events govern NK cell cytokine production and cellular cytotoxicity. While the activity of PI3K followed by the activation of mitogen-activated PK is known to be crucial for NK cell cytotoxicity, we here identified the AKT – mTOR pathway as a yet unknown central component in the regulation of NK cell IFN-γ production. Moreover, in light of the important role of NK cells in tumor immune surveillance our data indicate that the choise and dosing of the most suitable PKI for a given cancer patient requires careful consideration. In the future it will be critical to define potential differences in immunosuppressive and immunostimulatory side effects of different compounds among the rapidly growing assortment of multi-targeted PKI to enable therapeutic approaches combining targeting of crucial signaling pathways in tumor cells with immunotherapy. Disclosures: No relevant conflicts of interest to declare.

The impact of Fc engineering on an anti-CD19 antibody: increased Fcγ receptor affinity enhances B-cell clearing in nonhuman primates

Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3735-3743 ◽  
Author(s):  
Jonathan Zalevsky ◽  
Irene W. L. Leung ◽  
Sher Karki ◽  
Seung Y. Chu ◽  
Eugene A. Zhukovsky ◽  
...  
Keyword(s):  
B Cell ◽  
Nk Cells ◽  
Binding Affinity ◽  
Effector Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Fcγ Receptor ◽  
B Cell Malignancies ◽  
Cell Functions ◽  
The Impact

Abstract CD19, a B cell–restricted receptor critical for B-cell development, is expressed in most B-cell malignancies. The Fc-engineered anti-CD19 antibody, XmAb5574, has enhanced Fcγ receptor (FcγR) binding affinity, leading to improved FcγR-dependent effector cell functions and antitumor activity in murine xenografts compared with the non–Fc-engineered anti-CD19 IgG1 analog. Here, we use XmAb5574 and anti-CD19 IgG1 to further dissect effector cell functions in an immune system closely homologous to that of humans, the cynomolgus monkey. XmAb5574 infusion caused an immediate and dose-related B-cell depletion in the blood (to <10% of baseline levels) concomitant with a sustained reduction of natural killer (NK) cells. NK cells had fully recovered by day 15, whereas B-cell recovery was underway by day 57. B cells in secondary lymphoid tissues were depleted (to 34%-61% of vehicle), with involuted germinal centers apparent in the spleen. Anti-CD19 IgG1 had comparable serum exposure to XmAb5574 but demonstrated no B-cell depletion and no sustained NK-cell reduction. Thus, increasing FcγR binding affinity dramatically increased B-cell clearing. We propose that effector cell functions, possibly those involving NK cells, mediate XmAb5574 potency in cynomolgus monkeys, and that enhancing these mechanisms should advance the treatment of B-cell malignancies in humans.

Major role of the effector to target ratio in rituximab mediated B cell depletion and interferon-Γ production by NK cells: Relevance in NHL and B-cell CLL

2005 ◽  
Vol 23 (16_suppl) ◽  
pp. 2566-2566 ◽  
Author(s):  
S. Dall’ozzo ◽  
C. Kantari ◽  
G. Cartron ◽  
C. Le Guellec ◽  
P. Bardos ◽  
...  
Keyword(s):  
B Cell ◽  
Nk Cells ◽  
Interferon Γ ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Target Ratio

scholarly journals Essential role of the TNF-TNFR2 cognate interaction in mouse dendritic cell–natural killer cell crosstalk

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3333-3341 ◽  
Author(s):  
Jun Xu ◽  
Ayan K. Chakrabarti ◽  
Jennifer L. Tan ◽  
Lisheng Ge ◽  
Andrea Gambotto ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Contact ◽  
Cell Functions ◽  
Essential Components ◽  
Cell Crosstalk

Abstract Dendritic cells (DCs) and natural killer (NK) cells are essential components of the innate immune system and have a central role in initiation and regulation of adaptive immune responses. During the early critical immune activities, DCs and NK cells interact and reciprocally regulate each other via cell-cell contact. The molecular mediators of the DC–NK-cell crosstalk are largely undefined. In the present study, we show in mice that DC stimulation of NK-cell IFN-γ secretion requires DC membranebound but not secreted products; is increased by augmenting the expression of DC transmembrane tumor necrosis factor (tmTNF) and NK-cell transmembrane TNF receptor type 2 (tmTNFR2); is inhibited by blocking TNF or TNFR2 but not TNFR1; is impaired by knocking out DC Tnf or NK-cell Tnfr2 but not DC Tnfr1 or Tnfr2 and NK-cell Tnf or Tnfr1; and is restored in TNF-deficient DCs by reconstituting tmTNF, but cannot be mimicked by soluble TNF. We also demonstrate that DC TNF and NK-cell TNFR2 are required for DC-mediated NK-cell proliferation and amplification of cytotoxic activity. These novel findings provide the first evidence that DC–NK-cell crosstalk mediates enhancement of NK-cell functions via triggering NK-cell tmTNFR2 by DC tmTNF.

KS01.4.A NK cells as key orchestrators in mediating the anti-tumour response to immune checkpoint blockade in melanoma brain metastases

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii3-ii3
Author(s):  
C M Fife ◽  
J Williams ◽  
R Brownlie ◽  
T Andreou ◽  
A Sunderland ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Brain Metastases ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Immune Checkpoint Blockade ◽  
Cell Depletion

Abstract BACKGROUND Brain metastases (BrM) are an unmet clinical need with poor prognosis. 60% of melanoma patients develop BrM. BrM are strongly understudied due to frequent exclusion from clinical trials, and hence treatment options commonly lag behind. Antibodies targeting the immune-inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have demonstrated efficacy against melanoma BrM. Despite this, therapeutic responses are highly variable, and it is unknown why therapy fails in a high proportion of patients. Improved therapeutic strategies require a thorough understanding of potentially exploitable mechanisms of therapeutic efficacy. Our data previously implicated different immune cells, foremost CD8+ T cells, but also NK cells, in the intracranial efficacy and enhanced survival benefit of immune checkpoint blockade (ICB). Our aim here is to investigate the role of NK cells in mediating the response to ICB in melanoma BrM. MATERIAL AND METHODS To study the role of NK cells in the response to ICB in melanoma BrM, a tumour transplantation model of B16 melanoma with simultaneous extracranial (i.e., flank) and brain tumours in C57BL/6 mice was utilised. NK cells were depleted through administration of anti-asialo-GM1 NK cell-depleting antibodies. Confirmation of NK cell depletion and quantification of intratumoral immune cell populations was performed using flow cytometry. Intratumoral gene expression of key chemokines and immune mediator genes was assessed using RT-qPCR and mRNA-seq. RESULTS Highly variable response to ICB with respect to intratumoral accumulation of CD8+ T cells allowed separation of mice into responders and non-responders and revealed genes and pathways associated with response to ICB. NK cell depletion reversed the ICB-mediated increase in the accumulation of CD8+ T cells and significantly reduced the expression of genes associated with response in intracranial and extracranial tumours. The ICB-mediated significant increase in gene expression of various chemokines (i.e., Cxcl9/10) and immune mediators (i.e., Ifng, Prf1 and Gzmb) was significantly abrogated upon NK cell depletion. CONCLUSION NK cells play a critical role in the underlying mechanisms of ICB efficacy through their modulation of the tumour microenvironment and enhancement of CD8+ T cell accumulation in intracranial tumours. Targeting of NK cells may allow potentiation of ICB therapy in the brain, as well as at extracranial sites.

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