Polysaccharide enhanced NK cell cytotoxicity against pancreatic cancer via TLR4/MAPKs/NF-κB pathway in vitro/vivo

2019 ◽  
Vol 225 ◽  
pp. 115223 ◽  
Author(s):  
Xin Xie ◽  
Lingman Ma ◽  
Yiran Zhou ◽  
Wen Shen ◽  
Duiyue Xu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Nk Cell ◽  
Cell Cytotoxicity ◽  
Nk Cell Cytotoxicity

scholarly journals Enhancing NK cell-mediated cytotoxicity to cisplatin-resistant lung cancer cells via MEK/Erk signaling inhibition

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Li Yang ◽  
MingJing Shen ◽  
Li Jun Xu ◽  
Xiaodong Yang ◽  
Ying Tsai ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Death Receptor ◽  
Neutralizing Antibody ◽  
Erk Signaling ◽  
Cytotoxic Action ◽  
Cell Cytotoxicity ◽  
Nk Cell Cytotoxicity ◽  
Resistant Cells

Abstract Major progress has been made clinically in inhibiting the programmed death receptor 1 (PD-1)/PD-L1 interaction to enhance T cell-mediated immune function, yet the effectiveness of anti-PD-L1/PD-1 agents in enhancing natural killer (NK) cell’s function remains largely unknown. Susceptibilities of cisplatin-resistant A549CisR and H157CisR cells vs. parental cells to the cytotoxic action of NK cells were examined. We found cisplatin-resistant cells more resistant to NK cell cytotoxicity than parental cells. There were constitutively higher expressions of PD-L1 in A549CisR and H157CisR cells than in parental cells in vitro, as well as in H157CisR cell-derived tumors than H157P cell-derived tumors. In contrast, we observed that the expression of PD-1 in NK cells was induced after co-culture with cisplatin-resistant cells. We also observed increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity when neutralizing antibody of PD-1 or PD-L1 was added. Further, we found that the NK group 2, member D (NKG2D) ligand levels were lower in A549CisR and H157CisR cells than in parental cells. Meanwhile, we discovered that the MEK/Erk signaling pathway played a significant role in this regulation, and the addition of a MEK/Erk pathway inhibitor significantly enhanced the PD-L1 Ab effect in enhancing NK cell cytotoxicity to cisplatin-resistant cells.

In Vitro and In Vivo Sensitization of Malignant Cells to Autologous Natural Killer Cell Cytotoxicity Following Exposure to Bortezomib.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 925-925 ◽  
Author(s):  
Andreas Lundqvist ◽  
Kristy Greeneltch ◽  
Maria Berg ◽  
Shivani Srivastava ◽  
Nanae Harashima ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Cell Cytotoxicity ◽  
Malignant Cells ◽  
Nk Cell Cytotoxicity ◽  
Tumor Death

Abstract Killer IgG like receptor (KIR) inactivation of NK cells by self HLA molecules has been proposed as a mechanism through which malignant cells evade host NK cell-mediated immunity. To overcome this limitation, we sought to develop a method to sensitize the patient’s tumor to autologous NK cell cytotoxicity. The proteasome inhibitor bortezomib has recently been shown to enhance the activity of tumor death receptors. We found that exposure of a variety of different leukemia, lymphoma and solid tumor cancer cell lines to sub-apoptotic doses of bortezomib sensitized tumor cells in vitro to lysis by allogeneic NK cells. Importantly, this sensitizing effect also occurs with autologous NK cells normally rendered inactive via tumor KIR ligands; NK cells expanded from patients with metastatic renal cell carcinoma were significantly more cytotoxic against the patient’s own autologous tumor cells when pretreated with bortezomib compared to untreated tumors. This sensitization to autologous NK cell killing was also observed in vivo in two different murine tumor models. A significant delay in tumor growth in C57BL/6 mice bearing LLC1 tumors (figure) and a delay in tumor growth and a significant prolongation (p<0.01) in survival were observed in RENCA tumor bearing Balb/c mice treated with bortezomib and syngeneic NK cell infusions compared to untreated mice or animals treated with bortezomib alone or NK cells alone. An investigation into the mechanism through which NK cell cytotoxicity was potentiated revealed bortezomib enhanced the activity of tumor death receptor-dependent and -independent apoptotic pathways. More specifically, bortezomib sensitized human and murine tumor cells to TRAIL and perforin/granzyme mediated NK cell cytotoxicity respectively. These observations suggest that pretreatment of malignant cells with bortezomib could be used as a strategy to override NK cell inhibition via tumor KIR ligands, thus potentiating the activity of adoptively infused autologous NK cells. A clinical trial evaluating the safety and anti-tumor efficacy of adoptively infused autologous NK cells in patients with advanced malignancies with and without tumor sensitization using bortezomib is currently being explored. Figure: Tumor growth in LLC1 bearing C57BL/6 mice. Fourteen days following s.c. injection of 3x105 LLC1 tumor cells, mice received 15μg (i.p) bortezomib and/or an adoptive infusion of 1x106 NK cells from C57BL/6 mice (i.v) given on day 15. Each dot represents the tumor volume of individual mice measured on day 28 post tumor injection. Tumors were significantly smaller in mice treated with bortezomib followed by NK cells compared to controls or mice that received either NK cells alone or bortezomib alone (p<0.04 for all groups). Figure:. Tumor growth in LLC1 bearing C57BL/6 mice. . / Fourteen days following s.c. injection of 3x105 LLC1 tumor cells, mice received 15μg (i.p) bortezomib and/or an adoptive infusion of 1x106 NK cells from C57BL/6 mice (i.v) given on day 15. Each dot represents the tumor volume of individual mice measured on day 28 post tumor injection. Tumors were significantly smaller in mice treated with bortezomib followed by NK cells compared to controls or mice that received either NK cells alone or bortezomib alone (p<0.04 for all groups).

Effects of Emitted Qi on In Vitro Natural Killer Cell Cytotoxic Activity

2001 ◽  
Vol 29 (01) ◽  
pp. 17-22 ◽  
Author(s):  
Myeong Soo Lee ◽  
Hwa Jeong Huh ◽  
Hye-Sook Jang ◽  
Chang Sub Han ◽  
Hoon Ryu ◽  
...  
Keyword(s):  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Activity ◽  
K562 Cells ◽  
Target Cells ◽  
Cell Cytotoxicity ◽  
Nk Cell Activity ◽  
Nk Cell Cytotoxicity

The present study investigated the effects of Korean Qi-therapy, ChunSoo Energy Healing, on natural killer (NK) cell cytotoxicity in vitro depending on Qi-treatment time and the types of cells treated. NK cell cytotoxicity was assayed by measuring LDH release from tumor target cells (K562 cell lines). NK activity was significantly increased by emitted-Qi treatment of 30 sec duration. Three and 5 minutes of Qi projection created the greatest increase in NK cell activity when mixtures of NK cells and K562 cells were treated (1.81 and 2.12 fold for 4 hr culture; 1.54 and 1.36 for 16 hr culture, respectively). NK cell activity increased significantly in Qi-treated K562 cells alone (1.13 fold, p < 0.05) compared to control. These results are consistent with in vivo Qi-therapy on humans and suggests that emitted-Qi has an acute stimulatory effect on NK cell activity. This study provides direct scientific support that Qi as such may positively affect human cellular immunity.

Impaired NK cell cytotoxicity by high level of interferon-γ in concanavalin A-induced hepatitis

2005 ◽  
Vol 83 (11) ◽  
pp. 1045-1053 ◽  
Author(s):  
Zhongjun Dong ◽  
Cai Zhang ◽  
Haiming Wei ◽  
Rui Sun ◽  
Zhigang Tian
Keyword(s):  
Nk Cells ◽  
Cell Lines ◽  
Nk Cell ◽  
Interferon Γ ◽  
Cell Cytotoxicity ◽  
Wild Mice ◽  
Ifn Γ ◽  
Nk Cell Cytotoxicity

Unlike T cells, the role of natural killer (NK) cells is not well documented in the concanavalin (ConA)- induced hepatitis model. This study aimed to investigate the regulatory effect of high levels of interferon-γ (IFN-γ) on NK cells in ConA-induced hepatitis. The cytotoxicities of NK cells from ConA-injected mice or NK cell lines (NK92 and NKL) were detected by the 4-h 51Cr release assay. Depletion of NK cells with AsGM1 antibody was used to assess the NK cell role in ConA-induced hepatitis. Expression of NK cell receptors and cytotoxic molecules was measured by reverse transcription – polymerase chain reaction. Twelve hours after ConA injection, serum IFN-γ was significantly increased in wild mice, but not in severe combined immunodeficiency mice, and hepatic NK cells exerted impaired cytotoxicity against YAC-l cells in wild mice. Eight hours after NK cells were incubated in serum from ConA-treated mice, NK cell cytotoxicity was down-modulated and the effect was abolished by pretreatment with neutralizing serum IFN-γ with specific antibody in vitro. A high concentration of IFN-γ (> 1000 U/mL) inhibited the cytotoxicities of 2 NK cell lines in vitro, accompanied with down-regulation of NKG2D transcripts and up-regulation of NKG2A/B and KIR2DL transcripts. The inhibitive role of IFN-γ was not seen in NKG2D ligand negative cells. These results suggest that NK cell cytotoxicity was inhibited by high levels of IFN-γ in ConA-induced hepatitis, which may relate to the dispensable role of NK cells.Key words: cytotoxicity, hepatoimmunology, interferon-γ, liver injury.

scholarly journals Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells

Blood ◽  
2009 ◽  
Vol 113 (24) ◽  
pp. 6120-6127 ◽  
Author(s):  
Andreas Lundqvist ◽  
Hisayuki Yokoyama ◽  
Aleah Smith ◽  
Maria Berg ◽  
Richard Childs
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Nk Cells ◽  
Regulatory T Cell ◽  
Nk Cell ◽  
Treg Cells ◽  
Cell Cytotoxicity ◽  
Antitumor Effects ◽  
Nk Cell Cytotoxicity

Abstract Ligation of inhibitory receptors renders natural killer (NK) cells inactive against autologous tumors. Recently, the proteasome inhibitor bortezomib was shown to sensitize tumors to autologous NK-cell cytotoxicity in vitro. Here, we show bortezomib augments the antitumor effects of syngeneic NK-cell infusions in tumor-bearing animals; this effect is further enhanced in regulatory T cell (Treg cell)–depleted hosts. In vitro, bortezomib-treated tumors had higher tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and perforin/granzyme-mediated caspase-8 activity, which enhanced their susceptibility to NK-cell lysis. Bioluminescence imaging of mice with established tumors showed treatment with bortezomib and syngeneic NK cells reduced tumor growth and prolonged survival compared with controls receiving bortezomib or NK cells alone. In contrast, tumor progression was not delayed when animals received bortezomib and perforin-deficient NK cells, showing drug-induced augmentation in NK-cell cytotoxicity was mediated through perforin/granzyme. Furthermore, tumor growth was slower in bortezomib-treated recipients when host Treg cells were eradicated with anti-CD25 antibody before infusing NK cells compared with mice without Treg-cell ablation (tumor doubling time, 16.7 vs 4.9 days, respectively; P = .02). These findings suggest that depletion of Treg cells followed by bortezomib-induced tumor sensitization to autologous NK cells could be used as a novel strategy to treat cancer.

scholarly journals MicroRNA-20a mediates the cytotoxicity of natural killer cells in endometriosis via ERG/HLX/STAT4/perforin axis

2019 ◽  
Author(s):  
Li-Juan Chen ◽  
Bin Hu ◽  
Zhi-Qiang Han ◽  
Jian Ni ◽  
Yong-Ming Zhou ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nude Mice ◽  
Nk Cell ◽  
Protective Role ◽  
Cell Cytotoxicity ◽  
Nk Cell Cytotoxicity

Abstract Background: Intriguingly, microRNA-20a (miR-20a) has been recently witnessed to be involved in the pathogenesis of endometriosis (EMS) but the molecular mechanism controlled by miR-20a is to be undefined. The present study is designed to probe into how miR-20a acts to regulate the cytotoxicity of natural killer (NK) cells. Methods: Most of all, consistent with the clinical determination in EMS patients, miR-20a was determined to be down-regulated in NK cells isolated from nude mice. miR-20a could specifically bind to ERG and negatively regulates its expression in NK cells. Additionally, shRNA-mediated silencing of ERG decreased the expression of HLX. HLX up-regulated STAT4 by inducing proteasome degradation and inhibited NK cell cytotoxicity. Results: Of great importance, forced expression of miR-20a consequently induced NK cell cytotoxicity in vitro by increasing perforin expression via enhancement of STAT4 that was caused by impairing the binding of ERG to HLX enhancer. The in vivo experiments further confirmed the promoting role of miR-20a in the cytotoxicity of NK cells isolated from EMS nude mice and subsequent protective role of miR-20a against EMS-induced endometrial injury. Conclusion: The aforementioned data suggest that miR-20a potentiates the cytotoxicity of NK via up-regulating perforin mediated by ERG/HLX/STAT4, highlighting potential novel mechanisms associated with EMS progression.

scholarly journals β-Glucan-Induced IL-10 Secretion by Monocytes Triggers Porcine NK Cell Cytotoxicity

2021 ◽  
Vol 12 ◽  
Author(s):  
Leen Hermans ◽  
Steffi De Pelsmaeker ◽  
Sofie Denaeghel ◽  
Eric Cox ◽  
Herman W. Favoreel ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Target Cells ◽  
Cell Cytotoxicity ◽  
Tnf Α ◽  
Beta Glucans ◽  
Nk Cell Cytotoxicity ◽  
Molecular Patterns

Beta-glucans are naturally occurring polysaccharides present in cell walls of fungi, yeast, bacteria, cereals, seaweed, and algae. These microbe-associated molecular patterns (MAMPs) possess immunomodulatory properties. In human, it has been suggested that NK cells can be activated by β-glucans. Here, we aimed to elucidate whether β-glucans modulate porcine NK cell responses in vitro and if so, how these effects are mediated. We investigated the effect of two β-glucans, Macrogard and Curdlan, which differ in solubility and structure. Direct addition of β-glucans to purified porcine NK cells did not affect cytotoxicity of these cells against K562 target cells. However, when using PBMC instead of purified NK cells, β-glucan addition significantly increased NK cell-mediated cytotoxicity. This effect depended on factors secreted by CD14+ monocytes upon β-glucan priming. Further analysis showed that monocytes secrete TNF-α, IL-6, and IL-10 upon β-glucan addition. Of these, IL-10 turned out to play a critical role in β-glucan-triggered NK cell cytotoxicity, since depletion of IL-10 completely abrogated the β-glucan-induced increase in cytotoxicity. Furthermore, addition of recombinant IL-10 to purified NK cells was sufficient to enhance cytotoxicity. In conclusion, we show that β-glucans trigger IL-10 secretion by porcine monocytes, which in turn leads to increased NK cell cytotoxicity, and thereby identify IL-10 as a potent stimulus of porcine NK cell cytotoxicity.

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