scholarly journals Natural Killer Cells as Key Players of Tumor Progression and Angiogenesis: Old and Novel Tools to Divert Their Pro-Tumor Activities into Potent Anti-Tumor Effects

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 461 ◽  
Author(s):  
Barbara Bassani ◽  
Denisa Baci ◽  
Matteo Gallazzi ◽  
Alessandro Poggi ◽  
Antonino Bruno ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Nk Cells ◽  
Natural Killer ◽  
Cancer Progression ◽  
Nk Cell ◽  
Dual Function ◽  
Therapeutic Approaches ◽  
New Findings ◽  
Soluble Hla ◽  
The Impact

. Immune cells, as a consequence of their plasticity, can acquire altered phenotype/functions within the tumor microenvironment (TME). Some of these aberrant functions include attenuation of targeting and killing of tumor cells, tolerogenic/immunosuppressive behavior and acquisition of pro-angiogenic activities. Natural killer (NK) cells are effector lymphocytes involved in tumor immunosurveillance. In solid malignancies, tumor-associated NK cells (TANK cells) in peripheral blood and tumor-infiltrating NK (TINK) cells show altered phenotypes and are characterized by either anergy or reduced cytotoxicity. Here, we aim at discussing how NK cells can support tumor progression and how induction of angiogenesis, due to TME stimuli, can be a relevant part on the NK cell-associated tumor supporting activities. We will review and discuss the contribution of the TME in shaping NK cell response favoring cancer progression. We will focus on TME-derived set of factors such as TGF-β, soluble HLA-G, prostaglandin E2, adenosine, extracellular vesicles, and miRNAs, which can exhibit a dual function. On one hand, these factors can suppress NK cell-mediated activities but, on the other hand, they can induce a pro-angiogenic polarization in NK cells. Also, we will analyze the impact on cancer progression of the interaction of NK cells with several TME-associated cells, including macrophages, neutrophils, mast cells, cancer-associated fibroblasts, and endothelial cells. Then, we will discuss the most relevant therapeutic approaches aimed at potentiating/restoring NK cell activities against tumors. Finally, supported by the literature revision and our new findings on NK cell pro-angiogenic activities, we uphold NK cells to a key host cellular paradigm in controlling tumor progression and angiogenesis; thus, we should bear in mind NK cells like a TME-associated target for anti-tumor therapeutic approaches.

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.

scholarly journals A novel mechanism of natural killer cell response to anti-CTLA-4 therapy identified by integrative analysis of mouse and human tumors

2020 ◽  
Author(s):  
Emily F. Davis-Marcisak ◽  
Allison A. Fitzgerald ◽  
Michael D. Kessler ◽  
Ludmila Danilova ◽  
Elizabeth M. Jaffee ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Mouse Tumors ◽  
Natural Killer Cell Response ◽  
Melanoma Patients ◽  
Inhibitory Antibodies ◽  
The Impact

AbstractImmune checkpoint-inhibitory antibodies (ICIs) are well-established immunotherapies. Despite this, the impact of ICI therapy on non-T cell intratumoral immune cells is ill-defined, restraining the improvement of ICI efficacy. Preclinical murine models of human disease are infrequently validated in clinical trials, impairing the identification of novel biological factors impacting clinical ICI response. To address this barrier, we used our previously described computational approach that integrates high-throughput single-cell RNA sequencing datasets to identify known and novel cellular alterations induced by ICIs that are conserved in mice and humans. We found a signature of intratumoral natural killer (NK) cell activation that is enriched in anti-CTLA-4 treated mouse tumors and correlates with longer overall survival and is predictive of anti-CTLA-4 (ipilimumab) response in melanoma patients. We demonstrate that human NK cells express CTLA-4, which directly binds anti-CTLA-4. These data reveal a novel role for NK cells in anti-CTLA-4 treatment and present opportunities to enhance ICI efficacy. Importantly, we provide a new computational tool for onco-immunology that can identify and validate biological observations across species.

Natural Killer Cells Display an Activated Phenotype but Reduced Effector Functions in Obese Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3430-3430
Author(s):  
Sebastien Viel ◽  
Laurie Besson ◽  
Emily Charrier ◽  
Jacques Bienvenu ◽  
Emmanuel Disse ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Granzyme B ◽  
K562 Cells ◽  
Obese Patients ◽  
Activation Markers ◽  
Significant Difference ◽  
The Impact

Abstract The impact of adiposity on the immune system remains largely unexplored. While obesity has been suggested to be a predisposing or adverse prognostic factor in certain neoplastic diseases it is not yet clear to what extent this may involve the innate or adaptative immune systems. Adipose tissue produces a large number of secreted molecules, or adipocytokines, which may have immunomodulatory functions. This project aimed to determine whether phenotypical and/or functional properties of circulating natural killer (NK) cells were influenced by body mass index (BMI). In a preliminary study, 47 patients with no history of hematological malignancy were included, including 14 healthy volunteers with a normal BMI (18.5-25), 10 patients considered to be overweight (25 < BMI < 30), 11 patients considered as obese (BMI > 30) and 12 patients who were previously obese and had lost weight. Peripheral blood was analyzed by flow cytometry for the following markers: activating receptors (CD16, C161, DNAM-1, 2B4, NKG2C, NKG2D, NKp46, NKp30), inhibitor receptors (NKG2A, KIR2DL1, KIR2DL2, KIR3DL1), activation markers (CD69, granzyme B, NKG2C), maturation markers (CD56, CD57, CD94, CX3CR1) and cytotoxicity markers (perforin, NKG7). Moreover the capacity of NK cells to degranulate and to produce several cytokines (TNF, IFN-g) or chemokines (MIP1-b) in response to stimulation by K562 cells or Rituximab coated -tumor B cells was evaluated. Results showed a positive correlation between BMI and total number of circulating NK cells, with a significant difference between lean patients and obese patients. Immunophenotypic analyses showed that NKp46 and CD94 expression (measured by Mean Fluorescence Intensity) were both significantly reduced with increased BMI. NK cells from obese patients also show signs of activation, characterized by an elevation of the expression of CD69 and granzyme B and a reduction of the expression of CD16. The ability of NK cells to be activated in the presence of cell lines was also reduced in obese patients: NK cell secretion of IFN-g and MIP-1b in the presence of Granta cells or MIP-1b in the presence of K562 decreased linearly with increasing BMI. NK cell degranulation upon co-culture with K562 cells was also negatively correlated with BMI. In these different assays pre-obese and ex-obese patients scored intermediate between lean and obese patients. Overall these results suggest in vivo activation and exhaustion of NK cells in obese patients. These cells are thus potentially less likely to participate as effector cells in immunotherapeutic regimens. Disclosures No relevant conflicts of interest to declare.

Natural killer cell lytic activity and CD56dim and CD56bright cell distributions during and after intensive training

2004 ◽  
Vol 96 (6) ◽  
pp. 2167-2173 ◽  
Author(s):  
Masatoshi Suzui ◽  
Takeshi Kawai ◽  
Hiroko Kimura ◽  
Kazuyoshi Takeda ◽  
Hideo Yagita ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Lytic Activity ◽  
Cell Cytotoxicity ◽  
Intensive Training ◽  
Nk Cell Cytotoxicity ◽  
The Impact ◽  
Heavy Training

The purpose of this study was to examine the impact of intensive training for competitive sports on natural killer (NK) cell lytic activity and subset distribution. Eight female college-level volleyball players undertook 1 mo of heavy preseason training. Volleyball drills were performed 5 h/day, 6 days/wk. Morning resting blood samples were collected before training (Pre), on the 10th day of training (During), 1 day before the end of training (End), and 1 wk after intensive training had ceased (Post). CD3-CD16brightCD56dim (CD56dim NK), CD3-CD16dim/-CD56bright NK (CD56bright NK), and CD3+CD16-CD56dim (CD56dim T) cells in peripheral blood were determined by flow cytometry. The circulating count of CD56dim NK cells (the predominant population, with a high cytotoxicity) did not change, nor did the counts for other leukocyte subsets. However, counts for CD56bright NK and CD56dim T cells (subsets with a lower cytotoxicity) increased significantly ( P < 0.01) in response to the heavy training. Overall NK cell cytotoxicity decreased from Pre to End ( P = 0.002), with a return to initial values at Post. Lytic units per NK cell followed a similar pattern ( P = 0.008). Circulating levels of interleukin-6, interferon-γ, and tumor necrosis factor-α remained unchanged. These results suggest that heavy training can decrease total NK cell cytotoxicity as well as lytic units per NK cell. Such effects may reflect in part an increase in the proportion of circulating NK cells with a low cytotoxicity.

scholarly journals Interleukin-15-Stimulated Natural Killer Cells Clear HIV-1-Infected Cells following Latency ReversalEx Vivo

2018 ◽  
Vol 92 (12) ◽  
pp. e00235-18 ◽  
Author(s):  
Carolina Garrido ◽  
Maria Abad-Fernandez ◽  
Marina Tuyishime ◽  
Justin J. Pollara ◽  
Guido Ferrari ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Receptor Expression ◽  
Immune Recognition ◽  
Hiv Eradication ◽  
Infected Cells ◽  
Interleukin 15 ◽  
The Impact

ABSTRACTCurrent efforts toward human immunodeficiency virus (HIV) eradication include approaches to augment immune recognition and elimination of persistently infected cells following latency reversal. Natural killer (NK) cells, the main effectors of the innate immune system, recognize and clear targets using different mechanisms than CD8+T cells, offering an alternative or complementary approach for HIV clearance strategies. We assessed the impact of interleukin 15 (IL-15) treatment on NK cell function and the potential for stimulated NK cells to clear the HIV reservoir. We measured NK cell receptor expression, antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxicity, interferon gamma (IFN-γ) production, and antiviral activity in autologous HIV replication systems. All NK cell functions were uniformly improved by IL-15, and, more importantly, IL-15-treated NK cells were able to clear latently HIV-infected cells after exposure to vorinostat, a clinically relevant latency-reversing agent. We also demonstrate that NK cells from HIV-infected individuals aviremic on antiretroviral therapy can be efficiently stimulated with IL-15. Our work opens a promising line of investigation leading to future immunotherapies to clear persistent HIV infection using NK cells.IMPORTANCEIn the search for an HIV cure, strategies to enhance immune function to allow recognition and clearance of HIV-infected cells following latency reversal are being evaluated. Natural killer (NK) cells possess characteristics that can be exploited for immunotherapy against persistent HIV infection. We demonstrate that NK cells from HIV-positive donors can be strongly stimulated with IL-15, improving their antiviral and cytotoxic potential and, more importantly, clearing HIV-infected cells after latency reversal with a clinically relevant drug. Our results encourage further investigation to design NK cell-based immunotherapies to achieve HIV eradication.

Natural killer cells and cancer therapy, what we know and where we are going

Immunotherapy ◽  
2019 ◽  
Vol 11 (14) ◽  
pp. 1231-1251 ◽  
Author(s):  
Faezeh Ghaemdoust ◽  
Mahsa Keshavarz-Fathi ◽  
Nima Rezaei
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
The Body ◽  
Innate Immune ◽  
Regulatory Function ◽  
Therapeutic Approaches ◽  
Cell Immunotherapy ◽  
And Function ◽  
Cancer Immunosurveillance

Natural killer (NK) cells are among the significant components of innate immune system and they have come to the first line of defense against tumor cells developing inside the body. CD56lo/CD16+NK cells are highly cytotoxic and CD56hi NK cells can produce cytokines and perform a regulatory function. Specific features of NK cells have made them a unique choice for cancer immunotherapy. Simple interventions like cytokine-injection to boost the internal NK cells were the first trials to target these cells. Nowadays, many other types of intervention are under investigation, such as adoptive NK cell immunotherapy. In this paper, we will discuss the biology and function of NK cells in cancer immunosurveillance and therapeutic approaches against cancer via using NK cells.

147 CD155 blockade boosts alloreactive natural killer cell antitumor effects against osteosarcoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A160-A160
Author(s):  
Monica Cho ◽  
Madison Phillips ◽  
Longzhen Song ◽  
Amy Erbe ◽  
Christian Capitini
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Cancer Biology ◽  
Nk Cell ◽  
Allogeneic Bone ◽  
Cytotoxicity Assays ◽  
Allogeneic Bmt ◽  
The Impact

BackgroundPediatric patients with relapsed and refractory osteosarcoma have poor prognoses with few treatment options. Allogeneic bone marrow transplant (BMT) has not yet shown a graft-versus-tumor (GVT) effect for osteosarcoma. Natural killer (NK) cells demonstrate antitumor activity against osteosarcoma, but adoptively transferred NK cells have limited proliferation, cytotoxicity, and persistence in vivo. To enhance an NK-specific GVT effect, we propose blocking the poliovirus receptor CD155 checkpoint molecule, which is overexpressed on osteosarcoma and can engage both activating and inhibitory receptors on NK cells. The impact of CD155 blockade on GVT and graft-versus-host-disease (GVHD) is unknown.MethodsNK cells from C57BL/6 (B6) mice were expanded with recombinant IL-15/IL-15R and analyzed by flow cytometry. Cytotoxicity assays were performed with IL-15 expanded B6 NK cells and mKate2-expressing K7M2 murine osteosarcoma at a 1:1 ratio with blockade of CD155 and CD155 ligands. To test efficacy of NK cell infusion and CD155 blockade after allogeneic BMT, BALB/c mice were lethally irradiated, transplanted with allogeneic B6 bone marrow, and challenged with luciferase-expressing K7M2 on day 0. At day 7, mice received IL-15 expanded B6 NK cells intravenously with either anti-IgG control or anti-CD155 antibody intraperitoneally and IL-2 subcutaneously on days 7 and 11. Mice were monitored for tumor growth by bioluminescence, and toxicity by GVHD using weight loss and clinical scores.ResultsCompared to unexpanded murine NK cells, IL-15 expanded NK cells (n = 6) show increased expression of NKG2D (65.33 ± 10.77% NKG2D+, p = 0.0077; 1030 ± 177.0 MFI, p = 0.0101) and an increased ratio of the CD155 activating (CD226) to inhibitory (TIGIT) ligand expression (11.71 ± 4.121, p = 0.0362). In cytotoxicity assays with IL-15 expanded allogeneic murine NK cells (n = 3 replicates), CD155 blockade enhances K7M2 osteosarcoma lysis (60.62 ± 3.19%, p = 0.0189) compared to IgG control (29.01 ± 7.66%). CD226 blockade decreased tumor killing (10.62 ± 8.51%, p = 0.0053) compared to CD155 blockade. In vivo allogeneic murine NK cell infusion and anti-CD155 antibody treatment after allogeneic BMT decreased tumor area under the curve by 44.3% compared to IgG control, without exacerbating GVHD.ConclusionsThese findings demonstrate that blockade of CD155 enhances an allogeneic NK cell-specific GVT effect for osteosarcoma treatment without exacerbating GVHD. CD155 blockade has the potential to improve usage of allogeneic BMT and NK cell adoptive immunotherapy as a combination treatment for osteosarcoma, and perhaps other pediatric sarcomas.AcknowledgementsThis work was supported by grants from the National Institute of General Medical Sciences/NIH T32 GM008692 and Training in Cancer Biology Training Grant NIH T32 CA009135 (to MMC), St. Baldrick’s Stand up to Cancer (SU2C) Pediatric Dream Team Translational Research Grant SU2C-AACR-DT-27-17, NCI/NIH R01 CA215461, American Cancer Society Research Scholar Grant RSG- 18-104-01-LIB, and the Midwest Athletes Against Childhood Cancer (MACC) Fund (to CMC). SU2C is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. The contents of this article do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

scholarly journals Major Surgical Trauma Impairs the Function of Natural Killer Cells but Does Not Affect Monocyte Cytokine Synthesis

Life ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 13
Author(s):  
Roman M. Müller-Heck ◽  
Björn Bösken ◽  
Ivo Michiels ◽  
Marcel Dudda ◽  
Marcus Jäger ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Immune Defense ◽  
Major Surgery ◽  
Surgical Trauma ◽  
Ifn Γ ◽  
Cell Suppression ◽  
The Impact

Major traumatic and surgical injury increase the risk for infectious complications due to immune dysregulation. Upon stimulation with interleukin (IL) 12 by monocyte/macrophages, natural killer (NK) cells release interferon (IFN) γ that supports the elimination of the pathogen. In the present study, we investigated the impact of invasive spine surgery on the relationship between monocytes and NK cells upon exposure to Staphylococcus aureus. Mononuclear cells and serum were isolated from peripheral blood of patients before and up to 8 d after surgery and stimulated with inactivated S. aureus bacteria. NK cell and monocyte function were determined by flow cytometry. NK cells continuously lost their ability to produce IFN-γ during the first week after surgery independently from monocyte-derived IL-12 secretion. IFN-γ synthesis was minimal on day 8 and was associated with decreased expression of the IL-12 receptor and activation of transcription factors required for IFNG gene transcription. Addition of recombinant IL-12 could at least partially restore NK cell function. Pre-operative levels of growth/differentiation factor (GDF) 15 in the serum correlated with the extent of NK cell suppression and with hospitalization. Thus, NK cell suppression after major surgery might represent a therapeutic target to improve the immune defense against opportunistic infections.

Characteristics of Natural Killer Cell Interaction with Trophoblast Cells During Pregnancy

2020 ◽  
Vol 20 (3) ◽  
pp. 202-219
Author(s):  
Dmitry Olegovich Bazhenov ◽  
Evgeniya Valerevna Khokhlova ◽  
Larisa Pavlovna Viazmina ◽  
Kseniya Nikolaevna Furaeva ◽  
Valentina Anatolievna Mikhailova ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
First Trimester ◽  
Conditioned Media ◽  
Receptor Expression ◽  
Trophoblast Cells ◽  
Third Trimester ◽  
The Impact

Background:: Maternal natural killer cells (NK cells) are a prevailing leukocyte population in the uteroplacental bed. Current descriptions of the effect of cytokines from the placental microenvironment on the expression of receptors by trophoblast and NK cells are inadequate and contradictory. There is insufficient information about the ability of NK cells to migrate through trophoblast cells. Objective:: To assess the impact of conditioned media obtained during culturing of placentas from the first and the third trimesters of healthy pregnancies on the phenotype of trophoblast and NK cells and impact on adhesion and transmigration of NK cells through trophoblast cell layer. Results:: We established that conditioned media obtained from both first and third trimester placentas increased the intensity of CD106, CD49e, CD49a, CD31, CD51/61, and integrin β6 expression by trophoblast cells. Conditioned media obtained from first trimester placentas increased the intensity of CD11a, CD29, CD49d, CD58, CD29 expression by NK cells. The presence of conditioned media from third trimester placentas resulted in more intense CD29, CD49d, CD11a, CD29, CD49d, and CD58 expression by NK cells. Migration of NK cells through trophoblast cells in the presence of conditioned media from first trimester placentas was increased compared with the migration level in the presence of conditioned media from third trimester placentas. This may be associated with increased expression of CD18 by NK cells. Conclusion:: First trimester placental secretory products increase adhesion receptor expression by both trophoblast and NK cells. Under these conditions, trophoblast is capable of ensuring NK cell adhesion and transmigration.

scholarly journals Resistance of Janus Kinase-2 Dependent Leptin Signaling in Natural Killer (NK) Cells: A Novel Mechanism of NK Cell Dysfunction in Diet-Induced Obesity

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3370-3378 ◽  
Author(s):  
Heike Nave ◽  
Guenter Mueller ◽  
Britta Siegmund ◽  
Roland Jacobs ◽  
Thorsten Stroh ◽  
...  
Keyword(s):  
Body Weight ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
The Body ◽  
Janus Kinase ◽  
Mrna Levels ◽  
Rt Pcr ◽  
The Impact

Leptin acts not only as an anorexigenic hormone but also regulates cell-mediated immunity via leptin receptors (Ob-R) expressed on T and B lymphocytes. However, the impact of leptin on natural killer (NK) cells is currently elusive. We evaluated leptin effects on NK cells in relation to the body weight in rats using in vivo and in vitro approaches. Leptin was injected iv in male lean and diet-induced obese Lewis and F344 rats. NK cell numbers were analyzed in blood and spleen by fluorescence activated cell sorting and immunohistochemistry, and the activity of NK cells was measured by chromium release assay. Ob-R expression was investigated by confocal laser scanning and quantitative RT-PCR. To compare leptin-dependent intracellular signaling under basal and leptin- and tumor cell (MADB106)-stimulated conditions, intracellular target proteins of NK cells were evaluated by Western blotting. Number and distribution pattern of splenic NK cells were significantly different in lean and obese animals. Leptin administration resulted in a 4-fold higher stimulation of the NK activity in lean than obese animals. This was not due to a decreased expression of Ob-R because quantitative RT-PCR revealed significantly higher Ob-Rb mRNA levels in NK cells from obese rats. In contrast, postreceptor signaling is differentially abrogated in obese animals with significantly lower activation of postreceptor signaling components (Janus kinase-2p, protein kinase B pT308, AMPαpT172) after an in vivo leptin challenge. In conclusion, the results for the first time assign leptin a central role as a modulator of NK cell number and activity only in lean but not obese subjects. The differential role of leptin has important implications for the influence of body weight in the response to systemic inflammations and in the immunological defense of cancer.

Sign in / Sign up

Export Citation Format

Share Document