scholarly journals Cytotoxicity of Human Hepatic Intrasinusoidal CD56bright Natural Killer Cells against Hepatocellular Carcinoma Cells

2019 ◽  
Vol 20 (7) ◽  
pp. 1564 ◽  
Author(s):  
Shin Hwang ◽  
Jaeseok Han ◽  
Ji-Seok Baek ◽  
Eunyoung Tak ◽  
Gi-Won Song ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Fas Ligand ◽  
Nk Cell ◽  
Carcinoma Cells ◽  
Huh7 Cells ◽  
Ifn Γ ◽  
And Function ◽  
Hcc Cells

Hepatic intrasinusoidal (HI) natural killer (NK) cells from liver perfusate have unique features that are similar to those of liver-resident NK cells. Previously, we have reported that HI CD56bright NK cells effectively degranulate against SNU398 hepatocellular carcinoma (HCC) cells. Thus, the aim of this study was to further investigate the phenotype and function of HI NK cells. We found that HI CD56bright NK cells degranulated much less to Huh7 cells. HI CD56bright NK cells expressed NKG2D, NKp46, TNF-related apoptosis-inducing ligand (TRAIL), and FAS ligand (FASL) at higher levels than CD56dim cells. SNU398 cells expressed more NKG2D ligands and FAS and less PD-L1 than Huh7 cells. Blockade of NKG2D, TRAIL, and FASL significantly reduced the cytotoxicity of HI NK cells against SNU398 cells, but blockade of PD-L1 did not lead to any significant change. However, HI NK cells produced IFN-γ well in response to Huh7 cells. In conclusion, the cytotoxicity of HI CD56bright NK cells was attributed to the expression of NKG2D, TRAIL, and FASL. The results suggest the possible use of HI NK cells for cancer immunotherapy and prescreening of HCC cells to help identify the most effective NK cell therapy recipients.

scholarly journals An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3583
Author(s):  
Stefania Mantovani ◽  
Stefania Varchetta ◽  
Dalila Mele ◽  
Matteo Donadon ◽  
Guido Torzilli ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Protein A ◽  
Ligand Interaction ◽  
Cell Responses ◽  
Hcc Cells

Natural killer (NK) cells play a pivotal role in cancer immune surveillance, and activating the receptor/ligand interaction may contribute to control the development and evolution of hepatocellular carcinoma (HCC). We investigated the role of the natural killer group 2 member D (NKG2D) activating receptor and its ligand, the major histocompatibility complex class I chain-related protein A and B (MICA/B) in patients with cirrhosis and HCC subjected to surgical resection, patients with cirrhosis and no HCC, and healthy donors (HD). The NKG2D-mediated function was determined in peripheral blood (PB), in tumor-infiltrating lymphocytes (NK-TIL), and in matched surrounding liver tissue (NK-LIL). A group of patients treated with sorafenib because of clinically advanced HCC was also studied. A humanized anti-MICA/B monoclonal antibody (mAb) was used in in vitro experiments to examine NK cell-mediated antibody-dependent cellular cytotoxicity. Serum concentrations of soluble MICA/B were evaluated by ELISA. IL-15 stimulation increased NKG2D-dependent activity which, however, remained dysfunctional in PB NK cells from HCC patients, in line with the reduced NKG2D expression on NK cells. NK-TIL showed a lower degranulation ability than NK-LIL, which was restored by IL-15 stimulation. Moreover, in vitro IL-15 stimulation enhanced degranulation and interferon-γ production by PB NK from patients at month one of treatment with sorafenib. Anti-MICA/B mAb associated with IL-15 was able to induce PB NK cytotoxicity for primary HCC cells in HD and patients with HCC, who also showed NK-TIL degranulation for autologous primary HCC cells. Our findings highlight the key role of the NKG2D-MICA/B axis in the regulation of NK cell responses in HCC and provide evidence in support of a potentially important role of anti-MICA/B mAb and IL-15 stimulation in HCC immunotherapy.

TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2082-2089 ◽  
Author(s):  
Kazuyoshi Takeda ◽  
Erika Cretney ◽  
Yoshihiro Hayakawa ◽  
Tsuyoshi Ota ◽  
Hisaya Akiba ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Fas Ligand ◽  
Nk Cell ◽  
Cell Subpopulation ◽  
Newborn Mice ◽  
Trail Expression ◽  
Effector Molecule ◽  
Ifn Γ

AbstractTumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is a key effector molecule expressed by natural killer (NK) cells and has been shown to prevent tumor initiation, growth, and metastasis. Here we demonstrate that TRAIL is the dominant cytotoxic effector molecule expressed by NK cells in fetal mice. On birth and with age, NK cells develop full functional capacity, including the ability to secrete interferon γ (IFN-γ) and interleukin 13 (IL-13) and mediate perforin- and Fas ligand-mediated cytotoxicity. However, interestingly, a phenotypically immature TRAIL+ NK cell subpopulation is retained in the liver of adult mice, and its retention is dependent on IFN-γ but not dependent on host IL-12, IL-18, or endogenous host pathogens. Adoptive transfer of either adult liver or neonatal TRAIL+ NK cells resulted in the appearance of TRAIL- NK cells with a mature phenotype, suggesting that these TRAIL+ NK cells were indeed a precursor. Although inducers of IFN-γ stimulated TRAIL expression on mature NK cells, our data indicated that constitutive TRAIL expression was a hallmark of immature cytotoxic NK cells. This study is the first to describe the concomitant maturation of NK cell effector function with surface phenotype in vivo and implies an important defense role for NK cell TRAIL in the developing immune system.

scholarly journals A High-Salt Diet Disturbs the Development and Function of Natural Killer Cells in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Xiaokang Zeng ◽  
Yan Li ◽  
Weibiao Lv ◽  
Xinhuai Dong ◽  
Chong Zeng ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Molecular Mechanism ◽  
Nk Cell ◽  
Cell Subset ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Ifn Γ ◽  
And Function

A high-salt diet (HSD) is common worldwide and can lead to cardiovascular disease, chronic inflammation, and autoimmune diseases. Moreover, increasing evidence shows that HSD is closely related to a variety of immune diseases. Natural killer (NK) cells are important innate immune cells that directly kill their targets via degranulation and secretion of interferon gamma (IFN-γ). NK cells play a vital role in resisting viruses and preventing the malignant transformation of cells; however, whether HSD affects the development and function of NK cells has not yet been elucidated. Therefore, the purpose of the present study was to understand the effects of HSD on the development and function of NK cells, in addition to investigating the underlying molecular mechanism. Our results show that the number of NK cells in the spleen and lungs of HSD-fed mice was significantly reduced, which may be due to the inhibition of NK cell proliferation. Further, the development of NK cells in mice was evaluated, and it was found that HSD reduced the effective NK cell subset (CD27+CD11b-). Moreover, it was also found that the ability of NK cells to secrete CD107a and IFN-γ in HSD-fed mice was decreased following stimulation with RMA-S and YAC-1 tumor cells. Finally, the underlying molecular mechanism was evaluated, and it was found that HSD increased the production of reactive oxygen species (ROS) by NK cells, while the expression of CD122 was decreased, suggesting that HSD downregulates CD122 expression in NK cells via ROS signaling, thereby reducing the responsiveness to IL-15 and ultimately inhibiting NK cell function. The present research discovered a novel mechanism by which HSD inhibits the function of NK cells, providing an alternative avenue for the treatment of immune diseases caused by HSD.

scholarly journals T-BET and EOMES Accelerate and Enhance Functional Differentiation of Human Natural Killer Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Kiekens ◽  
Wouter Van Loocke ◽  
Sylvie Taveirne ◽  
Sigrid Wahlen ◽  
Eva Persyn ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Current Knowledge ◽  
Functional Differentiation ◽  
Cell Maturation ◽  
Hematopoietic Stem ◽  
And Function

T-bet and Eomes are transcription factors that are known to be important in maturation and function of murine natural killer (NK) cells. Reduced T-BET and EOMES expression results in dysfunctional NK cells and failure to control tumor growth. In contrast to mice, the current knowledge on the role of T-BET and EOMES in human NK cells is rudimentary. Here, we ectopically expressed either T-BET or EOMES in human hematopoietic progenitor cells. Combined transcriptome, chromatin accessibility and protein expression analyses revealed that T-BET or EOMES epigenetically represses hematopoietic stem cell quiescence and non-NK lineage differentiation genes, while activating an NK cell-specific transcriptome and thereby drastically accelerating NK cell differentiation. In this model, the effects of T-BET and EOMES are largely overlapping, yet EOMES shows a superior role in early NK cell maturation and induces faster NK receptor and enhanced CD16 expression. T-BET particularly controls transcription of terminal maturation markers and epigenetically controls strong induction of KIR expression. Finally, NK cells generated upon T-BET or EOMES overexpression display improved functionality, including increased IFN-γ production and killing, and especially EOMES overexpression NK cells have enhanced antibody-dependent cellular cytotoxicity. Our findings reveal novel insights on the regulatory role of T-BET and EOMES in human NK cell maturation and function, which is essential to further understand human NK cell biology and to optimize adoptive NK cell therapies.

scholarly journals Inhibition of Enhancer of zeste homolog 2 (EZH2) induces natural killer cell-mediated eradication of hepatocellular carcinoma cells

2018 ◽  
Vol 115 (15) ◽  
pp. E3509-E3518 ◽  
Author(s):  
Suresh Bugide ◽  
Michael R. Green ◽  
Narendra Wajapeyee
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Down Regulation ◽  
Nkg2d Ligands ◽  
Enhancer Of Zeste

Natural killer (NK) cell-mediated tumor cell eradication could inhibit tumor initiation and progression. However, the factors that regulate NK cell-mediated cancer cell eradication remain unclear. We determined that hepatocellular carcinoma (HCC) cells exhibit transcriptional down-regulation of NK group 2D (NKG2D) ligands and are largely resistant to NK cell-mediated eradication. Because the down-regulation of NKG2D ligands occurred at the transcriptional level, we tested 32 chemical inhibitors of epigenetic regulators for their ability to re-express NKG2D ligands and enhance HCC cell eradication by NK cells and found that Enhancer of zeste homolog 2 (EZH2) was a transcriptional repressor of NKG2D ligands. The inhibition of EZH2 by small-molecule inhibitors or genetic means enhanced HCC cell eradication by NK cells in a NKG2D ligand-dependent manner. Collectively, these results demonstrate that EZH2 inhibition enhances HCC eradication by NK cells and that EZH2 functions, in part, as an oncogene by inhibiting immune response.

scholarly journals Aberrant anti-viral response of natural killer cells in severe asthma

2020 ◽  
Vol 55 (5) ◽  
pp. 1802422
Author(s):  
Justine Devulder ◽  
Cécile Chenivesse ◽  
Valérie Ledroit ◽  
Stéphanie Fry ◽  
Pierre-Emmanuel Lobert ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Severe Asthma ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Asthma Patients ◽  
Ifn Γ

Rhinovirus infections are the main cause of asthma exacerbations. As natural killer (NK) cells are important actors of the antiviral innate response, we aimed at evaluating the functions of NK cells from severe asthma patients in response to rhinovirus-like molecules or rhinoviruses.Peripheral blood mononuclear cells from patients with severe asthma and healthy donors were stimulated with pathogen-like molecules or with the rhinoviruses (RV)-A9 and RV-2. NK cell activation, degranulation and interferon (IFN)-γ expression were analysed.NK cells from severe asthma patients were less cytotoxic than those from healthy donors in response to toll-like receptor (TLR)3, TLR7/8 or RV-A9 but not in response to RV-2 stimulation. Furthermore, when cultured with interleukin (IL)-12+IL-15, cytokines which are produced during viral infections, NK cells from patients with severe asthma were less cytotoxic and expressed less IFN-γ than NK cells from healthy donors. NK cells from severe asthmatics exhibited an exhausted phenotype, with an increased expression of the checkpoint molecule Tim-3.Together, our findings indicate that the activation of NK cells from patients with severe asthma may be insufficient during some but not all respiratory infections. The exhausted phenotype may participate in NK cell impairment and aggravation of viral-induced asthma exacerbation in these patients.

scholarly journals Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5758-5768 ◽  
Author(s):  
Saar Gill ◽  
Adrianne E. Vasey ◽  
Alysha De Souza ◽  
Jeanette Baker ◽  
Aaron T. Smith ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Rapid Development ◽  
Receptor Expression ◽  
Down Regulation ◽  
First Response ◽  
Control Tumor Growth ◽  
Control Tumor ◽  
Ifn Γ

Abstract Natural killer (NK) cells are potent anti-viral and antitumor “first responders” endowed with natural cytotoxicity and cytokine production capabilities. To date, attempts to translate these promising biologic functions through the adoptive transfer of NK cells for the treatment of cancer have been of limited benefit. Here we trace the fate of adoptively transferred murine NK cells and make the surprising observation that NK cells traffic to tumor sites yet fail to control tumor growth or improve survival. This dysfunction is related to a rapid down-regulation of activating receptor expression and loss of important effector functions. Loss of interferon (IFN)γ production occurs early after transfer, whereas loss of cytotoxicity progresses with homeostatic proliferation and tumor exposure. The dysfunctional phenotype is accompanied by down-regulation of the transcription factors Eomesodermin and T-bet, and can be partially reversed by the forced overexpression of Eomesodermin. These results provide the first demonstration of NK-cell exhaustion and suggest that the NK-cell first-response capability is intrinsically limited. Further, novel approaches may be required to circumvent the described dysfunctional phenotype.

scholarly journals TIM-3 Expression Is Downregulated on Human NK Cells in Response to Cancer Targets in Synergy with Activation

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2417 ◽  
Author(s):  
Tram N. Dao ◽  
Sagar Utturkar ◽  
Nadia Atallah Lanman ◽  
Sandro Matosevic
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Interferon Gamma ◽  
Nk Cell ◽  
Ex Vivo ◽  
Cell Dysfunction ◽  
Nk Cell Receptors ◽  
Ifn Γ

Among natural killer (NK) cell receptors, the T-cell immunoglobulin and mucin-containing domain (TIM-3) has been associated with both inhibitory and activating functions, depending on context and activation pathway. Ex vivo and in vitro, expression of TIM-3 is inducible and depends on activation stimulus. Here, we report that TIM-3 expression can be downregulated on NK cells under specific conditions. When NK cells are exposed to cancer targets, they synergize with stimulation conditions to induce a substantial decrease in TIM-3 expression on their surface. We found that such downregulation occurs following prior NK activation. Downregulated TIM-3 expression correlated to lower cytotoxicity and lower interferon gamma (IFN-γ) expression, fueling the notion that TIM-3 might function as a benchmark for human NK cell dysfunction.

scholarly journals Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 926 ◽  
Author(s):  
Stefania Mantovani ◽  
Barbara Oliviero ◽  
Stefania Varchetta ◽  
Dalila Mele ◽  
Mario U. Mondelli
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Escape ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Current Status ◽  
Tumor Immune Escape

Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

Contribution of Natural Killer Cells to Inhibition of Angiogenesis by Interleukin-12

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1612-1621 ◽  
Author(s):  
Lei Yao ◽  
Cecilia Sgadari ◽  
Keizo Furuke ◽  
Eda T. Bloom ◽  
Julie Teruya-Feldstein ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Primary Cultures ◽  
Interleukin 12 ◽  
Ifn Γ

Abstract Interleukin-12 (IL-12) inhibits angiogenesis in vivo by inducing interferon-γ (IFN-γ) and other downstream mediators. Here, we report that neutralization of natural killer (NK) cell function with antibodies to either asialo GM1 or NK 1.1 reversed IL-12 inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis in athymic mice. By immunohistochemistry, those sites where bFGF-induced neovascularization was inhibited by IL-12 displayed accumulation of NK cells and the presence of IP-10–positive cells. Based on expression of the cytolytic mediators perforin and granzyme B, the NK cells were locally activated. Experimental Burkitt lymphomas treated locally with IL-12 displayed tumor tissue necrosis, vascular damage, and NK-cell infiltration surrounding small vessels. After activation in vitro with IL-12, NK cells from nude mice became strongly cytotoxic for primary cultures of syngeneic aortic endothelial cells. Cytotoxicity was neutralized by antibodies to IFN-γ. These results document that NK cells are required mediators of angiogenesis inhibition by IL-12, and provide evidence that NK-cell cytotoxicity of endothelial cells is a potential mechanism by which IL-12 can suppress neovascularization.

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