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Natural Killer Cells and Current Applications of Chimeric Antigen Receptor-Modified NK-92 Cells in Tumor Immunotherapy

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Natural Killer Cells and Current Applications of Chimeric Antigen Receptor-Modified NK-92 Cells in Tumor Immunotherapy International Journal of Molecular Sciences Review Natural Killer Cells and Current Applications of Chimeric Antigen Receptor-Modified NK-92 Cells in Tumor Immunotherapy Jianguang Zhang, Huifang Zheng and Yong Diao * School of Medicine, Huaqiao University, Quanzhou 362021, Fujian, China; [email protected] (J.Z.); [email protected] (H.Z.) * Correspondence: [email protected]; Tel.: +86-595-2269-2516 Received: 15 November 2018; Accepted: 11 January 2019; Published: 14 January 2019 Abstract: Natural killer (NK) cells are innate immune cells that can be activated rapidly to target abnormal and virus-infected cells without prior sensitization. With significant advancements in cell biology technologies, many NK cell lines have been established. Among these cell lines, NK-92 cells are not only the most widely used but have also been approved for clinical applications. Additionally, chimeric antigen receptor-modified NK-92 cells (CAR-NK-92 cells) have shown strong antitumor effects. In this review, we summarize established human NK cell lines and their biological characteristics, and highlight the applications of NK-92 cells and CAR-NK-92 cells in tumor immunotherapy. Keywords: natural killer cell line; NK-92; chimeric antigen receptor; immunotherapy; tumor 1. Introduction Natural killer (NK) cells are innate immune cells that were first discovered in mice in 1975 [1]. NK cells account for approximately 10% of lymphocytes in human peripheral blood (PB). Owing to the distinct chemokine receptors expressed in NK cells, the distributions of NK cells differ among healthy tissues. Most NK cells are found in the PB, liver, spleen, and bone marrow, and a small portion are also present in the lymph nodes [2–5]. NK cells are part of the first line of defense that protects the body from pathogen invasion and malignant transformation. When normal cells are infected by viruses, NK cells are rapidly activated to protect against abnormal and virus-infected cells, without prior sensitization [5–7]. In recent studies, as our understanding of tumor immunology has deepened, the basic research and clinical applications of NK cells has become an interesting topic. Some studies have shown that allogeneic NK cells have stronger tumor killing ability than autologous NK cells [8]. Moreover, allogeneic NK cells can be obtained from many sources, such as bone marrow, human embryonic stem cells, induced pluripotent stem cells, PB, and umbilical cord blood. However, these NK cells are difficult to purify and expand in vitro. With the gradual advancement of cell cloning technology, many NK cell lines have been established, including KHYG-1, NK-92, NKL, NKG, and YT cells. All of these cell lines are characterized by a uniform phenotype, high purity, and function, consistent with the general characteristics of NK cells. These cells can also be cultured at a large scale in vitro, thus providing sufficient cells for research and clinical applications. Among these cell lines, NK-92 cells are the most widely used line that have been approved for clinical use. Additionally, chimeric antigen receptor (CAR)-modified NK-92 (CAR-NK-92) cells have shown strong antitumor effects. In this review, we summarize the established human NK cell lines and their biological characteristics and highlight the applications of NK-92 cells and CAR-NK-92 cells in tumor immunotherapy. Int. J. Mol. Sci. 2019, 20, 317; doi:10.3390/ijms20020317 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 317 2 of 20 Int. J. Mol. Sci. 2019, 20, x 2 of 20 2.2. ReceptorReceptor DistributionDistribution andand KillingKilling MechanismMechanism ofof NKNK CellsCells AsAs the body's body’s first first line line of of defense, defense, many many surface surface molecules molecules (Figure (Figure 1) are1) are expressed expressed on NK on NKcells cells[9,10], [9 which,10], which are characterized are characterized by the expression by the expression of CD56 and of CD56 CD16 andcell surface CD16 cellmarkers, surface and markers, absence andof T-cell absence receptor of T-cell (TCR) receptor and B-cell (TCR) receptor. and B-cell According receptor. to differences According in toCD56 differences and CD16 in CD56expression and CD16density, expression two major density, subsets two of NK major cells subsets can be distin of NKguished, cells can i.e., be CD56bright distinguished, and i.e.,CD56dim CD56bright [3,5,11,12]. and CD56dimCD56dim [NK3,5, 11cells,12 ].are CD56dim fully mature, NK cells account are fully for approximately mature, account 90% for of approximately the NK cells 90%in the of PB, the NKand cellspredominantly in the PB, andmediate predominantly cytotoxici mediatety responses cytotoxicity [5]. CD56dim responses cells [5]. CD56dimcan play cellsroles canin playantibody- roles independent antibody-dependent cell-mediated cell-mediated cytotoxicity (ADCC) cytotoxicity through (ADCC) the surface through expression the surface of expressionCD16 (FcγRIII) of CD16 [13– (Fc15].γ RIII)CD56bright [13–15]. cells CD56bright are immature, cells are account immature, for approximately account for approximately 5–15% of the NK 5–15% cells of in the the NK PB, cells and inare the predominant PB, and are in predominant tissues and secondary in tissues lymphoid and secondary organs lymphoid[16]. CD56bright organs cells [16]. express CD56bright high levels cells expressof CD56, high CD94/NKG2A, levels of CD56, L-selectin, CD94/NKG2A, and a high-affinityL-selectin, interleukin and a high-affinity (IL)-2 receptor, interleukin but little (IL)-2 to receptor,no CD16 butand little killer-cell to no CD16 immunoglobulin-like and killer-cell immunoglobulin-like receptor. Therefore, receptor. CD56bright Therefore, cells CD56bright function cellsprimarily function to primarilysecrete cytokines, to secrete such cytokines, as interferon- such asγ, interferon-tumor necrosisγ, tumor factor necrosis (TNF)- factorα, and (TNF)- granulocyteα, and macrophage- granulocyte macrophage-colony-stimulatingcolony-stimulating factor [11,17]. factor [11,17]. FigureFigure 1. MajorMajor receptors receptors expressed expressed on on the the surface surface of natural of natural killer killer (NK) (NK) cells. cells. NKp46, NKp46, natural natural killer killercell p46-related cell p46-related protein; protein; NKp44, natural NKp44, killer natural cell p44-related killer cell p44-relatedprotein; NKp30, protein; natural NKp30, killer cell natural p30- killerrelated cell protein; p30-related CD, protein;Cluster CD,of differentiation Cluster of differentiation;; NKG2, also NKG2,known also as knownCD159; asKIR, CD159; killer-cell KIR, killer-cellimmunoglobulin-like immunoglobulin-like receptor; receptor;TIGIT, T TIGIT,cell immunoreceptor T cell immunoreceptor with Ig withand ITIM Ig and domains; ITIM domains; LAG3, LAG3,lymphocyte lymphocyte activation activation gene gene3 protein; 3 protein; TIM3, TIM3, T cell T cell immunoglobulin immunoglobulin mucin mucin receptor receptor 3; 3; PD1, programmedprogrammed cellcell deathdeath protein protein 1; 1; KLRG1, KLRG1, killer killer cell cell lectin-like lectin-like receptor receptor subfamily subfamily G memberG member 1;IL-2R, 1; IL- β interleukin-22R, interleukin-2 receptor; receptor; TGF TGFR, transformingβR, transforming growth growth factor factor beta beta receptors. receptors. NK cells do not express antigen-specific recognition receptors. There are two receptors with NK cells do not express antigen-specific recognition receptors. There are two receptors with opposite functions on their surface. The first type of receptor can bind to its corresponding ligand opposite functions on their surface. The first type of receptor can bind to its corresponding ligand on on the surface of the target cell, activating the killing effects of NK cells. This receptor is called the the surface of the target cell, activating the killing effects of NK cells. This receptor is called the activating NK cell receptor [18]. The other type of receptor, called the inhibitory NK cell receptor, activating NK cell receptor [18]. The other type of receptor, called the inhibitory NK cell receptor, inhibits the killing effect of NK cells [18]. inhibits the killing effect of NK cells [18]. Both the activating receptor and inhibitory receptor can recognize classical or nonclassical major Both the activating receptor and inhibitory receptor can recognize classical or nonclassical major histocompatibility complex (MHC) class I molecules expressed on the surface of normal cells. Inhibitory histocompatibility complex (MHC) class I molecules expressed on the surface of normal cells. receptors play a primary role in preventing NK cells from killing normal cells [19,20]. In virus-infected Inhibitory receptors play a primary role in preventing NK cells from killing normal cells [19,20]. In cells and tumor cells, MHC class I molecules on the cell surface are lost or downregulated; activating virus-infected cells and tumor cells, MHC class I molecules on the cell surface are lost or NK cell receptors play a leading role in this process. downregulated; activating NK cell receptors play a leading role in this process. Activated NK cells exert cytotoxic effects mainly through three pathways (Figure2). The first Activated NK cells exert cytotoxic effects mainly through three pathways (Figure 2). The first pathway is the perforin/granzyme pathway [9]. In this pathway, granzymes and perforin stored in pathway is the perforin/granzyme pathway [9]. In this pathway, granzymes and perforin stored in the cytoplasmic granules of NK cells are released by
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