• Molecules and Cells
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• v.24 no.1
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• pp.1-8
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• 2007

Natural killer (NK) cells play a crucial role in innate immune system and tumor surveillance. NK cells are derived from $CD34^+$hematopoietic stem cells and undergo differentiation via precursor NK cells in bone marrow (BM) through sequential acquisition of functional surface receptors. During differentiation of NK cells, many factors are involved including cytokines, membrane factors and transcription factors as well as microenvironment of BM. NK cells express their own repertoire of receptors including activating and inhibitory receptors that bind to major histocompatibility complex (MHC) class I or class I-related molecules. The balance between activating and inhibitory receptors determines the function of NK cells to kill targets. Binding of NK cell inhibitory receptors to their MHC class I-ligand renders the target cells to be protected from NK cell-mediated cytotoxicity. Thus, NK cells are able to discriminate self from non-self through MHC class I-binding inhibitory receptor. Using intrinsic properties of NK cells, NK cells are emerging to apply as therapeutic agents against many types of cancers. Recently, NK cell alloactivity has also been exploited in killer cell immunoglobulin-like receptor mismatched haploidentical stem cell transplantation to reduce the rate of relapse and graft versus host disease. In this review, we discuss the basic mechanisms of NK cell differentiation, diversity of NK cell receptors, and clinical applications of NK cells for anti-cancer immunotherapy.

• Hanyang Medical Reviews
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• v.33 no.1
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• pp.59-64
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• 2013

Cancer remains the leading cause of death worldwide despite intense efforts in developing innovative treatments. Current approaches in cancer therapy are mainly directed to a selective targeting of cancer cells to avoid potential side effects associated with conventional therapy. In this respect, Natural killer (NK) cells have gained growing attention and are now being considered as promising therapeutic tools for cancer therapy owing to their intrinsic ability to rapidly recognize and kill cancer cells, while sparing normal healthy cells. NK cells play a key role in the first line of defense against transformed and virus-infected cells. NK cells sense their target through a whole array of receptors, both activating and inhibitory. Functional outcome of NK cell against target cells is determined by the balance of signals transmitted from diverse activating and inhibiting receptors. Despite significant progress made in the role of NK cells attack as a pivotal sentinel in tumor surveillance, the molecular has been that regulate NK cell responses remain unclear, which restricts the use of NK cells as a therapeutic measure. Accordingly, current efforts for NK cell-based cancer therapy have largely relied on the strategies that are based on the manipulation of inhibitory receptor function. However, if we better understand the mechanisms governing NK cell activation, including those mediated by diverse activating receptors, this knowledge can be applied to the development of optimal design for cancer immunotherapy by targeting NK cells.

• IMMUNE NETWORK
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• v.23 no.1
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• pp.8.1-8.13
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• 2023

CD8⁺ T cells are activated by TCRs that recognize specific cognate Ags, while NK-cell activation is regulated by a balance between signals from germline-encoded activating and inhibitory NK receptors. Through these different processes of Ag recognition, CD8⁺ T cells and NK cells play distinct roles as adaptive and innate immune cells, respectively. However, some human CD8⁺ T cells have been found to express activating or inhibitory NK receptors. CD8⁺ T-cell populations expressing NK receptors straddle the innate-adaptive boundary with their innate-like features. Recent breakthrough technical advances in multi-omics analysis have enabled elucidation of the unique immunologic characteristics of these populations. However, studies have not yet fully clarified the heterogeneity and immunological characteristics of each CD8⁺ T-cell population expressing NK receptors. Here we aimed to review the current knowledge of various CD8⁺ T-cell populations expressing NK receptors, and to pave the way for delineating the landscape and identifying the various roles of these T-cell populations.

• Biomedical Science Letters
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• v.29 no.3
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• pp.178-183
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• 2023

Natural killer (NK) cells are innate cytotoxic lymphoid cells that actively prevent neoplastic development, growth, and metastatic dissemination in a process called cancer immunosurveillance. Regulation of the cytotoxic activity of NK cells relies on integrated interactions between inhibitory receptors and numerous activating receptors that act in tandem to eliminate tumor cells efficiently. Conventional chemotherapy is designed to produce an anti-proliferative or cytotoxic effect on early tumor cell division. Therapies designed to kill cancer cells and simultaneously maintain host anti-tumor immunity are attractive strategies for controlling tumor growth. Depending on the drug and dose used, several chemotherapeutic agents cause DNA damage and cancer cell death through apoptosis, immunogenic cell death, or other forms of non-killing (i.e., mitotic catastrophe, senescence, autophagy). Among stress-induced immunostimulatory proteins, changes in the expression levels of NK cell activating and inhibitory ligands and tumor cell death receptors play an important role in the detection and elimination by innate immune effectors including NK cells. Therefore, we will address how these cytotoxic lymphocytes sense and respond to high and low concentrations of drug-induced stress to the drug cisplatin, among the various types of drugs that contribute to their anticancer activity.

• IMMUNE NETWORK
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• v.12 no.6
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• pp.240-246
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• 2012

Natural killer (NK) cells play a pivotal role in early surveillance against virus infection and cellular transformation, and are also implicated in the control of inflammatory response through their effector functions of direct lysis of target cells and cytokine secretion. NK cell activation toward target cell is determined by the net balance of signals transmitted from diverse activating and inhibitory receptors. A distinct feature of NK cell activation is that stimulation of resting NK cells with single activating receptor on its own cannot mount natural cytotoxicity. Instead, specific pairs of co-activation receptors are required to unleash NK cell activation via synergy- dependent mechanism. Because each co-activation receptor uses distinct signaling modules, NK cell synergy relies on the integration of such disparate signals. This explains why the study of the mechanism underlying NK cell synergy is important and necessary. Recent studies revealed that NK cell synergy depends on the integration of complementary signals converged at a critical checkpoint element but not on simple amplification of the individual signaling to overcome intrinsic activation threshold. This review focuses on the signaling events during NK cells activation and recent advances in the study of NK cell synergy.

• Journal of Acupuncture Research
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• v.33 no.1
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• pp.47-56
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• 2016

Objectives : This study examined the effects of Bee venom on apoptosis in NCI-H157 human lung cancer cells and for promoting the apoptosis effects of Natural killer cell. Methods : Bee venom and Natural killer-92 cells were cultured either separately from or together with NCI-H157 cells for 24 hours. To figure out whether Bee venom enhances the cytotoxic effect of Natural Killer-92 cells, a cell viability assay was conducted. To observe the changes in Death receptors, apoptotic regulatory proteins and Nuclear $Factor-{\kappa}B$, western blot analysis was conducted. To observe the effect of Bee venom through an extrinsic mechanism, a transfection assay was conducted. Results : 1. Natural killer-92 cells and Bee venom significantly inhibited the growth of NCI-H157 cells and co-culture had more inhibitory effect than the separate culture. 2. Expressions of Fas, DR3, DR6, Bax, caspase-3, caspase-8, cleaved caspase-3, cleaved caspase-8 were increased, and expressions of Bcl-2 and cIAP were decreased. More efficacy was observed in co-culture than in separate culture. 3. Nuclear $Factor-{\kappa}B$ activation was clearly decreased. And co-culture showed much less activation than separate culture. 4. As a result of treatment for DR-siRNA, the reduced cell viability of NCI-H157 cells and the activity of Nuclear $Factor-{\kappa}B$ were increased. With this, it can be seen that Bee venom and Natural killer-92 cells have an effect on the cancer cells through the extrinsic mechanism. Conclusion : Bee venom is effective in inhibiting the growth of human lung cancer cells. Furthermore Bee venom effectively enhances the functions of Natural killer cells.

• Biomolecules & Therapeutics
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• v.19 no.2
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• pp.206-210
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• 2011

Natural Killer (NK) cells are the lymphocytes that are derived from hematopoietic stem cells, developed in the bone marrow from hematopoietic stem cells (HSC) by sequential acquisition of functional surface receptors, and express the repertoire of inhibitory and activating receptors. Recently, Osteopontin (OPN) has been identified as a critical factor for differentiation of natural killer cells. However, the detailed mechanism of OPN-induced NK differentiation has been still to be elucidated. Here, we determined the signaling pathway and possible receptor for OPN in NK differentiation. OPN induced expression of Bcl-2 and activation of Erk kinase. Inhibition of Erk pathway decreased the effect of OPN on NK differentiation. In addition, the expression of integrin ${\alpha}9$ was significantly increased by OPN during NK differentiation, suggesting the possible role of a major signaling molecule for OPN- induced NK differentiation.

• BMB Reports
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• v.54 no.1
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• pp.44-58
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• 2021

Natural killer (NK) cells, key antitumor effectors of the innate immune system, are endowed with the unique ability to spontaneously eliminate cells undergoing a neoplastic transformation. Given their broad reactivity against diverse types of cancer and close association with cancer prognosis, NK cells have gained considerable attention as a promising therapeutic target for cancer immunotherapy. NK cell-based therapies have demonstrated favorable clinical efficacies in several hematological malignancies but limited success in solid tumors, thus highlighting the need to develop new therapeutic strategies to restore and optimize anti-tumor activity while preventing tumor immune escape. The current therapeutic modalities yielding encouraging results in clinical trials include the blockade of immune checkpoint receptors to overcome the immune-evasion mechanism used by tumors and the incorporation of tumor-directed chimeric antigen receptors to enhance NK cell anti-tumor specificity and activity. These observations, together with recent advances in the understanding of NK cell activation within the tumor microenvironment, will facilitate the optimal design of NK cell-based therapy against a broad range of cancers and, more desirably, refractory cancers.

• IMMUNE NETWORK
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• v.4 no.4
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• pp.205-215
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• 2004

In the early host defense system, effector function of natural killer (NK) cells results in natural killing against target cells such as microbe-infected, malignant, and certain allogenic cells without prior stimulation. NK cell cytotoxicity is selectively regulated by homeostatic prevalence between a repertoire of both activating and inhibitory receptors, and the discrimination of untransformed cells is achieved by recognition of major histocompatibility complex (MHC) class I alleles through inhibitory signals. Although it is well known that the bipotential T/NK progenitors are derived from the common precusor, functional mechanisms in terms of the development of NK cells remain to be further investigated. NK cells are mainly involved in innate immunity, but recent studies have been reported that they also play a critical role in adaptive immune responses through interaction with dendritic cells (DC). This interaction will provide effector functions and development of NK cells, and elucidation of its precise mechanism may lead to therapeutic strategies for effective treatment of several immune diseases.

• Journal of Ginseng Research
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• v.48 no.3
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• pp.341-345
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• 2024

The objective of the study is to estimate the potential of gintonin, as an immune enhancing agent through natural killer cell (NK cell) activity in cyclophosphamide (CY)-induced immunosuppressive animals. Accumulated results reveals that, gintonin attenuated CY-induced immunosuppression and it might modulate NK cell activity to boost the immunity.