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Tarazona, Raquel, Nelson Lopez-Sejas, Beatriz Guerrero, Fakhri Hassouneh, Isabel Valhondo, Alejandra Pera, Beatriz Sanchez-Correa, et al. "Current progress in NK cell biology and NK cell-based cancer immunotherapy." Cancer Immunology, Immunotherapy 69, no. 5 (March 4, 2020): 879–99. http://dx.doi.org/10.1007/s00262-020-02532-9.
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Beaulieu, Aimee M., Natalie A. Bezman, Jang Eun Lee, Mehrdad Matloubian, Joseph C. Sun, and Lewis L. Lanier. "MicroRNA function in NK-cell biology." Immunological Reviews 253, no. 1 (April 2, 2013): 40–52. http://dx.doi.org/10.1111/imr.12045.
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Thomas, Louis, and Eric Long. "NK cell licensing modulates NK cell conjugation to target cells via altered activation receptor function (P1063)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 121.3. http://dx.doi.org/10.4049/jimmunol.190.supp.121.3.
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Abstract MHC class I recognition by inhibitory receptors on natural killer (NK) cells promotes a state of increased NK cell responsiveness through a process known as licensing/education. In the absence of either MHC class I expression or inhibitory receptors, NK cells exhibit a decreased responsive state. Thus NK cell licensing is a critical aspect of NK cell biology. However, understanding how licensing modulates natural cytotoxicity is limited. Using pure populations of unlicensed human NK cells, we were able to evaluate the effect of licensing on several NK cell functions. Our findings reveal that NK cell licensing does not affect lytic granule polarization but significantly enhances NK cell conjugation to target cells. Furthermore, our data show that activation receptors in unlicensed NK cells fail to provide strong ‘inside-out’ signaling for the beta2 integrin LFA-1. NK cell adhesion to target cells is a crucial initial step in NK cell-mediated cytotoxicity. The reduced conjugation of unlicensed NK cells may contribute to their hyporesponsive state.
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Stanietsky, Noa, and Ofer Mandelboim. "Paired NK cell receptors controlling NK cytotoxicity." FEBS Letters 584, no. 24 (September 7, 2010): 4895–900. http://dx.doi.org/10.1016/j.febslet.2010.08.047.
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Schönberg, Kathrin, Janna Rudolph, Isabelle Cornez, Peter Brossart, and Dominik Wolf. "The JAK1/JAK2 Inhibitor Ruxolitinib Substantially Affects NK Cell Biology." Blood 122, no. 21 (November 15, 2013): 16. http://dx.doi.org/10.1182/blood.v122.21.16.16.
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Abstract Introduction We recently demonstrated that ruxolitinib (INCB018424), the first approved JAK1/JAK2 inhibitor for treatment of myelofibrosis (MF), exerts potent anti-inflammatory activity. This may at least in part explain higher infection rates observed in ruxolitinib-treated patients. NK cells are critical for cancer-immune surveillance and cytokine-mediated signals are central for proper NK cell activation. We here aimed to characterize in detail the effects of JAK1/2 inhibition on human NK cells. Methods Highly purified CD56+ NK cells were isolated from human peripheral buffy coats by magnetic bead isolation and subsequently exposed to increasing concentrations of ruxolitinib (0.1-10 µM). Cytokine (1000U/ml IL-2, 25ng/ml IL-15)-induced NK cell proliferation was analyzed by CFSE dilution. Phenotypic and functional NK cell activation markers (NKp46, NKG2D, Granzyme B, CD16, and CD69) were analyzed by flow cytometry (including CD107a expression for degranulation). NK cell function was tested by flow-cytometry-based killing assays and quantification of IFN-γ production upon stimulation with either MHC class I-deficient K562 target cells or cytokines (IL-12, IL-18). In addition, phenotypic and functional analyses were also tested during NK receptor activation via plate-bound activating NKp46 antibodies. Signaling events were analyzed by Western Blot analysis to detect phosphorylation of JAK1 and JAK2 as well as by applying phospho-flow technology to evaluate ruxolitinib-mediated changes of cytokine-dependent signalling cascades (pS6, pSTAT1, pSTAT3, pSTAT5, pERK, pAKT, pP38, and pZAP70). Results Our results demonstrate provide first evidence that ruxolitinib profoundly affects cytokine-induced NK cell activation. This includes a significant and dose-dependent reduction of NK cell proliferation, reduced induction of activation-associated surface markers (including NKp46, NKG2D, Granzyme B, CD16, CD69) as well as impaired killing activity against the classical NK target cell line K562. In addition, all main functional activities of NK cells are down-regulated as shown by reduced cytotoxic capacity, impaired degranulation and IFN-γ production. After wash-out, the inhibitory effects of ruxolitinib on NK cells are fully reversible, as shown by proper re-activation by cytokines. In contrast to cytokine-mediated NK cell activation, stimulation via the NK-specific receptor NKp46 are not affected by ruxolitinib. Of note, ruxolitinib does not affect NK cell viability. On a molecular level, phospho-flow analyses revealed that cytokine associated signaling events, such as phosphorylation of STAT5 and S6 were dose-dependently reduced by ruxolitinib in primary human NK cells. Conclusions Ruxolitinib strongly inhibits NK cell activation leading to impaired proliferation and functional activity. Experiments verifying these effects in patients are currently ongoing and will be presented at the meeting. Our findings may have important clinical implications, when considering the application of ruxolitinib as GvHD therapy, because NK cells are critically involved in the GvL effect after allogeneic stem cell transplantation. Disclosures: Wolf: Novartis: Honoraria, Research Funding.
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Gardiner, Clair M. "NK cell metabolism." Journal of Leukocyte Biology 105, no. 6 (January 24, 2019): 1235–42. http://dx.doi.org/10.1002/jlb.mr0718-260r.
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Vojvodic, Svetlana, and Stevan Popovic. "Natural killer cells: Biology, functions and clinical relevance." Medical review 63, no. 1-2 (2010): 91–97. http://dx.doi.org/10.2298/mpns1002091v.
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Introduction. Natural Killer cells (NK cells) represent the subset of peripheral lymphocytes that play critical role in the innate immune response to virus-infected and tumor transformed cells. Lysis of NK sensitive target cells could be mediated independently of antigen stimulation and without requirement of peptide presentation by the major histocompatibility complex (MHC) molecules. NK cell activity and functions are controlled by a considerable number of cell surface receptors, which exist in both inhibitory and activating isoforms. There are several groups of NK cell surface receptors: 1) killer immunoglobulin like receptors-KIR, 2) C-type lectin receptors,3)natural citotoxicity receptors-NCR and 4) Toll-like receptors-TLR. Functions of NK receptors. Defining the biology of NK cell surface receptors has contributed to the concept of the manner how NK cells selectively recognize and lyse tumor and virally infected cells while sparing normal cells. Further, identification of NK receptor ligands and their expression on the normal and transformed cells has led to the development of clinical approaches to manipulating receptor/ligand interactions that showed clinical benefit. NK cells are the first lymphocyte subset that reconstitute the peripheral blood following allogeneic HSCT and multiple roles for alloreactive donor NK cells have been demonstrated, in diminishing Graft vs. Host Disease (GvHD) through selective killing recipient dendritic cells, prevention of graft rejection by killing recipient T cells and participation in Graft vs. Leukaemia (GvL) effect through destruction of residual host tumor cells. Conclusion. Besides their role in HSCT, NK cell receptors have an important clinical relevance that reflects from the fact that they play a crucial role in the development of some diseases as well as in possibilities of managing all NK receptors through selective expansion and usage of NK cells in cancer immunotherapy.
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Terrén, Iñigo, Ane Orrantia, Idoia Mikelez-Alonso, Joana Vitallé, Olatz Zenarruzabeitia, and Francisco Borrego. "NK Cell-Based Immunotherapy in Renal Cell Carcinoma." Cancers 12, no. 2 (January 29, 2020): 316. http://dx.doi.org/10.3390/cancers12020316.
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Natural killer (NK) cells are cytotoxic lymphocytes that are able to kill tumor cells without prior sensitization. It has been shown that NK cells play a pivotal role in a variety of cancers, highlighting their relevance in tumor immunosurveillance. NK cell infiltration has been reported in renal cell carcinoma (RCC), the most frequent kidney cancer in adults, and their presence has been associated with patients’ survival. However, the role of NK cells in this disease is not yet fully understood. In this review, we summarize the biology of NK cells and the mechanisms through which they are able to recognize and kill tumor cells. Furthermore, we discuss the role that NK cells play in renal cell carcinoma, and review current strategies that are being used to boost and exploit their cytotoxic capabilities.
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Clara, Joseph A., Robert Reger, Mala Chakraborty, Steven L. Highfill, Jianjian Jin, David F. Stroncek, and Richard W. Childs. "Cell Density of NK Cells during Ex Vivo Expansion Impacts NK Cell Surface TRAIL Expression." Blood 136, Supplement 1 (November 5, 2020): 5–6. http://dx.doi.org/10.1182/blood-2020-141487.
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Introduction Natural Killer (NK) cells are an emerging form of cancer immunotherapy currently being tested in clinical trials world-wide. NK cells are innate immune cells that can kill tumor cells via release of cytotoxic granules and via surface expression of the death receptor ligands tumor-related apoptosis-inducing ligand (TRAIL) and Fas ligand. We and others have recently shown that the proteasome inhibitor bortezomib sensitizes tumor cells to NK cell TRAIL-mediated killing by upregulation of death receptor 5. In a recent phase I NK cell dose-escalation study conducted at the NIH (NCT00720785) we have attempted to exploit TRAIL sensitization by administering ex vivo-expanded autologous NK cells to patients with solid tumors or hematologic malignancies that have been pretreated with bortezomib. Ex vivo cultures used to expand clinical grade NK cells for this trial utilize irradiated EBV-LCL feeder cells and IL-2 containing media which upregulates surface expression of TRAIL, substantially augmenting NK cell killing of bortezomib-treated tumors in vitro. Here we characterize the impact of specific expansion conditions used to generate high numbers of NK cells for clinical use on NK cell TRAIL expression. Methods To generate clinical grade ex vivo-expanded NK cells, we first isolated NK cells from patient apheresis products by CD3+ depletion followed by CD56+ selection, and stimulated these enriched NK cells with irradiated EBV-LCL feeder cells at a ratio of 1:10 in X-VIVO 20 supplemented with 10% inactivated human AB serum and recombinant human IL-2 (500 IU/ml). The clinical trial evaluated 8 escalating NK cell dose levels (Figure 1). Cohorts 1-4 received a single infusion of ex vivo-expanded NK cells on day 0 in a dose-escalating fashion (3-6 pts per cohort) and cohorts 5-7 received 1 x 108 NK cells/kg on day 0 and a second escalating dose of NK cells infused on day +5. A "closed bag" Baxter PL732 culture system was used for cohorts 1-7 which was later changed to a GREX500-CS (Wilson Wolf) system in cohorts 7-8. Using flow cytometry, we monitored surface expression of TRAIL on the day NK cells were harvested and infused fresh into patients. We also assessed TRAIL expression on NK cells from a single patient cultured at 6 different cell densities (range: 2.03-16.95 x 106/cm2) using culture conditions mimicking the phase I trial. Results A total of 137 NK cell cultures were harvested and administered fresh to 32 patients. NK cells on the day of harvest expanded a median of 198-fold, 895-fold, and 3637-fold on culture days 14-16, 19-22, and 24-27, respectively. NK cells at harvest contained a median of 99.7% CD3−/CD56+ NK cells, were 68.65% CD16+ and had a median of 88% viability. TRAIL was assessed by mean fluorescence intensity (MFI) with a median surface expression of of 1245 (range 132-4913) at the time of infusion (Figure 1). Expansions for cohort 8 generated 10-14 x109 (1 vessel) and 50-70 x109 NK cells (4-5 vessels) for fresh infusion, enough to support the target dose level of 1x108 (1st harvest) and 5x108 (2nd harvest) NK cells/kg. Remarkably, NK cells grown at higher cell density to reach the target cell numbers for cohort 8 exhibited substantially reduced TRAIL expression (median: 255, range 132-691). Subsequent experiments conducted on NK cells expanded in vitro for 14 days at different cell densities/concentrations showed TRAIL expression (MFI range: 319-1627) inversely correlated with both cell density and concentration (Figure 2). NK cells grown at the highest cell density (16.95 x 106/cm2) and concentration (4.23 x 106/mL) expressed the least amount of TRAIL (MFI 319), in contrast to those cultured at the lowest cell density (2.03 x 106/cm2) and concentration (0.51 x 106/mL), which demonstrated a TRAIL MFI of 1627. Conclusions Although ex vivo cultures using feeder cells make it possible to expand large numbers of NK cells for clinical use in humans, the higher concentrations and density of cells in these cultures reduce NK cell surface expression of TRAIL. In vitro, TRAIL expression appears to inversely correlate with cell density. These data highlight the need to avoid overly concentrating ex vivo expanded NK cells to maximize TRAIL surface expression as a method to potentiate the anticancer effects of adoptively infused NK cells. Disclosures No relevant conflicts of interest to declare.
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Lee, Barclay J., and Emily M. Mace. "Acquisition of cell migration defines NK cell differentiation from hematopoietic stem cell precursors." Molecular Biology of the Cell 28, no. 25 (December 2017): 3573–81. http://dx.doi.org/10.1091/mbc.e17-08-0508.
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Human natural killer (NK) cells are generated from CD34+ precursors and can be differentiated in vitro by coculture with developmentally supportive stromal cells. We have previously described the acquisition of cell migration as a feature of NK cell terminal maturation in this system. Here we perform continuous long-term imaging and tracking of NK cell progenitors undergoing in vitro differentiation. We demonstrate that NK cell precursors can be tracked over long time periods on the order of weeks by utilizing phase-contrast microscopy and show that these cells acquire increasing motility as they mature. Additionally, we observe that NK cells display a more heterogeneous range of migratory behaviors at later stages of development, with the acquisition of complex modes of migration that are associated with terminal maturation. Together these data demonstrate previously unknown migratory behaviors of innate lymphocytes undergoing lineage differentiation revealed by long-term imaging and analysis workflows.
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Martin-Antonio, Beatriz, Erica Serrano, Guillermo Suñe, Lorena Perez, Marcos Calderón, Jose María Estanyol, Amer Najjar, Clara Bueno, Carlos Fernandez de Larrea, and Alvaro Urbano-Ispizua. "Cell-Cell Communication Between Multiple Myeloma (MM) Cells and Cord Blood Derived NK Cells (CB-NK) Regulates Both Tumor Cell Death and Tumor Cell Survival." Blood 126, no. 23 (December 3, 2015): 1787. http://dx.doi.org/10.1182/blood.v126.23.1787.1787.
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Abstract In previous work we have demonstrated that CB-NK exert a cytotoxicity towards MM cells which involves lipid-protein vesicle transfer, which it is secondarily transferred from recipient MM cells to neighboring MM cells. This transmissible cytotoxicity causes a 5-7% of neighboring MM cell death (CDD 2015;22(1):96-107). However, this transmission between MM cells could have a diluent effect of the CB-NK cytotoxicity which could be also a tumor cell survival mechanism. To further analyze this mechanism, we determined the proteins transferred between cells and the role of lipids in this transfer. We performed TRANS-SILAC proteomics using two different approaches: 1) Labeling CB-NK cells with heavy amino-acids (hAA) to identify both CB-NK proteins transferred to MM (1ºMM) and secondary CB-NK proteins transferred from 1ºMM to neighboring MM cells (2ºMM). 2) Labeling MM cells, before CB-NK contact, with hAA to identify transferred proteins from 1ºMM to 2ºMM cells, and from 1ºMM to CB-NK. We found that 1ºMM cells acquired 9.5% of CB-NK proteins, and that these proteins were transferred to 2ºMM cells. As a consequence, 1ºMM cells diluted the CB-NK proteins from 9.5% to 3.8%; which represented 7.2% of proteins in 2ºMM cells. In the second approach, we observed that, MM cells transferred to neighboring MM cells only 1.9% of MM proteins in resting conditions. However, in the presence of CB-NK, this transfer was increased up to 7.7%. Furthermore, CB-NK cells acquired 7.3% of 1ºMM proteins. These findings demonstrate a secondary CB-NK protein transfer between MM cells, which represents a CB-NK protein dilution content from 1ºMM to 2ºMM, and an increased transfer of 1ºMM proteins to 2ºMM (Fig.1A). Proteomic analysis showed that transferred proteins were involved in FAS signaling, apoptosis, inflammation, chromatin organization, glycolysis, spliceosome, and rRNA metabolic process. Among these proteins we focused on histones and the 14-3-3 family which are associated to both cell death and cell survival. Confocal microscopy confirmed transfer of histones and 14-3-3 proteins. Protein transfer occurred within neutral lipid vesicles-structures. We also observed that MM cells were inter-connected with a much higher number of neutral lipid structures (nanotubes and bigger structures similar to bags) than in K562 cells (Fig. 1B). Thus, we next analyzed the role of these neutral lipids in MM cell-cell communication. The cholesterol synthesis and lipid transport inhibitor U18666A significantly decreased the number of these lipid connective structures between MM cells, and it was toxic for MM cells. Furthermore, breaking the lipid connection between MM cells with U18666A increased CB-NK cytotoxicity (p<0.05). These effects were not observed in K562 cells. This could be explained by a blockage of the diluent effect mediated by MM cells of the proteins and lipids from CB-NK cells. Last, we analyzed apoptotic levels of 1ºMM cells after co-culture with 2ºMM cells, and the apoptotic levels of the remaining 2ºMM cells. Both populations became early apoptotic, however, after 3-5 days they recovered from early apoptosis, decreasing from 36% of early apoptotic cells to 3%, which was their apoptotic basal levels, and most importantly, without causing cell death, as no difference in the cell number in comparison to control MM cells was observed. Therefore, our data demonstrate that this diluent transmission effect between MM cells might be a new cell mechanism that contributes to tumor cell survival. Importantly, because lipid structures mediate this diluent transmission effect, this tumor cell survival mechanism might be eliminated by using lipid metabolism inhibitors. In conclusion, cell-cell communication increases when MM cells are stressed because of CB-NK presence. Although this causes a transmissible cytotoxicity in a small % of MM cells, a diluent effect also occurs between cells helping MM cells to recover and promoting MM cell survival. Lipid structures play an important role in this cell-cell communication, which may represent a new therapeutic target for MM treatment. Disclosures No relevant conflicts of interest to declare.
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Gunduz, Mehmet, Pinar Ataca Atilla, and Erden Atilla. "New Orders to an Old Soldier: Optimizing NK Cells for Adoptive Immunotherapy in Hematology." Biomedicines 9, no. 9 (September 11, 2021): 1201. http://dx.doi.org/10.3390/biomedicines9091201.
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NK (Natural Killer) cell-mediated adoptive immunotherapy has gained attention in hematology due to the progressing knowledge of NK cell receptor structure, biology and function. Today, challenges related to NK cell expansion and persistence in vivo as well as low cytotoxicity have been mostly overcome by pioneering trials that focused on harnessing NK cell functions. Recent technological advancements in gene delivery, gene editing and chimeric antigen receptors (CARs) have made it possible to generate genetically modified NK cells that enhance the anti-tumor efficacy and represent suitable “off-the-shelf” products with fewer side effects. In this review, we highlight recent advances in NK cell biology along with current approaches for potentiating NK cell proliferation and activity, redirecting NK cells using CARs and optimizing the procedure to manufacture clinical-grade NK and CAR NK cells for adoptive immunotherapy.
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Mowbray, J. F., and B. A. Croy. "Meeting on NK cell biology, Clamart, France, 1996." Journal of Reproductive Immunology 33, no. 1 (April 1997): 27–29. http://dx.doi.org/10.1016/s0165-0378(97)01019-x.
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Farag, Sherif S., Todd A. Fehniger, Loredana Ruggeri, Andrea Velardi, and Michael A. Caligiuri. "Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect." Blood 100, no. 6 (September 15, 2002): 1935–47. http://dx.doi.org/10.1182/blood-2002-02-0350.
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AbstractNatural killer (NK) cells have held great promise for the immunotherapy of cancer for more than 3 decades. However, to date only modest clinical success has been achieved manipulating the NK cell compartment in patients with malignant disease. Progress in the field of NK cell receptors has revolutionized our concept of how NK cells selectively recognize and lyse tumor and virally infected cells while sparing normal cells. Major families of cell surface receptors that inhibit and activate NK cells to lyse target cells have been characterized, including killer cell immunoglobulinlike receptors (KIRs), C-type lectins, and natural cytotoxicity receptors (NCRs). Further, identification of NK receptor ligands and their expression on normal and transformed cells completes the information needed to begin development of rational clinical approaches to manipulating receptor/ligand interactions for clinical benefit. Indeed, clinical data suggest that mismatch of NK receptors and ligands during allogeneic bone marrow transplantation may be used to prevent leukemia relapse. Here, we review how NK cell receptors control natural cytotoxicity and novel approaches to manipulating NK receptor-ligand interactions for the potential benefit of patients with cancer.
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Lee, Hansol, Inês Pires Da Silva, Umaimainthan Palendira, Richard A. Scolyer, Georgina V. Long, and James S. Wilmott. "Targeting NK Cells to Enhance Melanoma Response to Immunotherapies." Cancers 13, no. 6 (March 17, 2021): 1363. http://dx.doi.org/10.3390/cancers13061363.
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Natural killer (NK) cells are a key component of an innate immune system. They are important not only in initiating, but also in augmenting adaptive immune responses. NK cell activation is mediated by a carefully orchestrated balance between the signals from inhibitory and activating NK cell receptors. NK cells are potent producers of proinflammatory cytokines and are also able to elicit strong antitumor responses through secretion of perforin and granzyme B. Tumors can develop many mechanisms to evade NK cell antitumor responses, such as upregulating ligands for inhibitory receptors, secreting anti-inflammatory cytokines and recruiting immunosuppressive cells. Enhancing NK cell responses will likely augment the effectiveness of immunotherapies, and strategies to accomplish this are currently being evaluated in clinical trials. A comprehensive understanding of NK cell biology will likely provide additional opportunities to further leverage the antitumor effects of NK cells. In this review, we therefore sought to highlight NK cell biology, tumor evasion of NK cells and clinical trials that target NK cells.
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Sungur, Can M., and William J. Murphy. "Utilization of mouse models to decipher natural killer cell biology and potential clinical applications." Hematology 2013, no. 1 (December 6, 2013): 227–33. http://dx.doi.org/10.1182/asheducation-2013.1.227.
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Abstract Natural killer (NK) cells represent a key component of innate immunity. The utility of mouse models to recapitulate the human immune response has been a matter of ongoing debate, especially with regard to NK cells. However, mouse models of NK cells have provided significant advancements in our understanding of the biology of the cells that bridge these species. Initial characterization of NK cell activity was in mouse hematopoietic stem cell transplantation models. Recent findings include uncovering functionally disparate subsets of NK cells based on unique inhibitory receptor expression patterns, the existence of memory-like NK cells, and immunoregulatory NK cells that affect hematopoiesis and T-cell function. In addition, the biology of these cells with regard to MHC-binding receptors that affect NK cell subset maturation and function in the context of licensing, the importance of cytokines such as IL-15 in their development and maintenance, and evidence of NK exhaustion have been initially studied in mice. Many of these findings have been validated in clinical studies and demonstrate the significant wealth of knowledge that can be obtained by mouse models. However, it is important to understand the limitations and conditions of the mouse models, particularly when studying NK cells in hematopoietic stem cell transplantation and cancer.
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Orrantia, Ane, Iñigo Terrén, Gabirel Astarloa-Pando, Olatz Zenarruzabeitia, and Francisco Borrego. "Human NK Cells in Autologous Hematopoietic Stem Cell Transplantation for Cancer Treatment." Cancers 13, no. 7 (March 30, 2021): 1589. http://dx.doi.org/10.3390/cancers13071589.
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Natural killer (NK) cells are phenotypically and functionally diverse lymphocytes with the ability to recognize and kill malignant cells without prior sensitization, and therefore, they have a relevant role in tumor immunosurveillance. NK cells constitute the main lymphocyte subset in peripheral blood in the first week after hematopoietic stem cell transplantation (HSCT). Although the role that NK cells play in allogenic HSCT settings has been documented for years, their significance and beneficial effects associated with the outcome after autologous HSCT are less recognized. In this review, we have summarized fundamental aspects of NK cell biology, such as, NK cell subset diversity, their effector functions, and differentiation. Moreover, we have reviewed the factors that affect autologous HSCT outcome, with particular attention to the role played by NK cells and their receptor repertoire in this regard.
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Mace, Emily M., and Jordan S. Orange. "Emerging insights into human health and NK cell biology from the study of NK cell deficiencies." Immunological Reviews 287, no. 1 (December 18, 2018): 202–25. http://dx.doi.org/10.1111/imr.12725.
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Burton, RC, YC Smart, R. Thorn, and HJ Winn. "Studies on natural killer (NK) cells IV NK-3·1: A new NK cell specific alloantigen." Immunology and Cell Biology 67, no. 5 (October 1989): 303–10. http://dx.doi.org/10.1038/icb.1989.45.
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Sun, Kai, Isabel Barao, Doug Redelman, and William Murphy. "NK Cell-Mediated Rejection of Bone Marrow Cells- In Vivo Evidence of NK Cell Subset Licensing." Blood 114, no. 22 (November 20, 2009): 3537. http://dx.doi.org/10.1182/blood.v114.22.3537.3537.
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Abstract Abstract 3537 Poster Board III-474 Natural killer (NK) cells have been shown to attack virally-infected and transformed cells as well allogeneic bone marrow cells (BMC) but not normal self-tissues. The mechanism of missing self recognition and self tolerance of NK cells is poorly understood. NK cells exist as subsets based on expression of inhibitory receptors (Ly49 in mouse, KIR in man) that bind MHC class molecules. In vitro data have shown that murine NK cell subsets bearing Ly49 receptors for self MHC class I molecules have intrinsically higher effector function, supporting the hypothesis that NK cells undergo a host MHC class I-dependent functional education, allowing the NK cells bearing the appropriate Ly49 receptors to preferentially mediate effector function. Thus far, no in vivo evidence for this preferential licensing or arming has been shown. We assessed the intrinsic response potential of the different Ly49+ NK cell subsets in BMC rejection without having the complicating effects of binding MHC on the target cell (which delivers potent inhibitory signals to the NK cell) by using β2-microglobulin deficient (β2m−/−) mice as donors which totally lack class I MHC molecules. Using syngeneic, congenic, and allogeneic strains of mice as recipients and depleting the different Ly49 subsets, we found that NK cell subsets whose Ly49 molecules have been shown to bind “self-MHC Class I” (ie Ly49G2 in H2d and Ly49C in H2b haplotypes) were found to be the dominant subset responsible for mediating the rejection of the β2m−/− BMC. This provides the first in vivo evidence for host MHC class I-dependent functional education (licensing or arming). Importantly, we also demonstrated that prior activation of the NK cells in vivo could override this licensing effect and allow the “non-licensed subset” to mediate rejection. The pattern of NK mediated rejection ability by Ly49 subsets was observed in B10D2 allogeneic H2d strain mice but not observed in BALB/c allogeneic H2d strain mice indicating that licensing ability was not solely dependent on host MHC expression and supporting the role of MHC class I–independent system for NK-cell self-tolerance. Interestingly, all H2d strain mice (B10.D2, BALB/c, and B6D2F1) were able to resist significantly greater amounts of B2m-/- BMC than H2b strain mice indicating that the rheostat hypothesis regarding Ly49 affinities for MHC and NK cell function impacts BMC rejection capability. These results demonstrate that both MHC and non-MHC genes on the host has multiple effects on NK cell subset-mediated BMC rejection and that licensing or arming of Ly49 NK cell subsets can be observed in vivo. Disclosures: No relevant conflicts of interest to declare.
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Straub, Christian, Marie-Luise Neulen, Beatrice Sperling, Katharina Windau, Maria Zechmann, Christine A. Jansen, Birgit C. Viertlboeck, and Thomas W. Göbel. "Chicken NK cell receptors." Developmental & Comparative Immunology 41, no. 3 (November 2013): 324–33. http://dx.doi.org/10.1016/j.dci.2013.03.013.
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Verma, Divya, Mukesh Verma, and Rangnath Mishra. "Stem Cell Therapy and Innate Lymphoid Cells." Stem Cells International 2022 (August 2, 2022): 1–12. http://dx.doi.org/10.1155/2022/3530520.
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Innate lymphoid cells have the capability to communicate with other immune cell types to coordinate the immune system functioning during homeostasis and inflammation. However, these cells behave differently at the functional level, unlike T cells, these cells do not need antigen receptors for activation because they are activated by the interaction of their receptor ligation. In hematopoietic stem cell transplantation (HSCT), T cells and NK cells have been extensively studied but very few studies are available on ILCs. In this review, an attempt has been made to provide current information related to NK and ILCs cell-based stem cell therapies and role of the stem cells in the regulation of ILCs as well. Also, the latest information on the differentiation of NK cells and ILCs from CD34+ hematopoietic stem cells is covered in the article.
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Spaggiari, Grazia Maria, Andrea Capobianco, Stelvio Becchetti, Maria Cristina Mingari, and Lorenzo Moretta. "Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation." Blood 107, no. 4 (February 15, 2006): 1484–90. http://dx.doi.org/10.1182/blood-2005-07-2775.
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In recent years, mesenchymal stem cells (MSCs) have been shown to inhibit T-lymphocyte proliferation induced by alloantigens or mitogens. However, no substantial information is available regarding their effect on natural killer (NK) cells. Here we show that MSCs sharply inhibit IL-2-induced proliferation of resting NK cells, whereas they only partially affect the proliferation of activated NK cells. In addition, we show that IL-2-activated NK cells (but not freshly isolated NK cells) efficiently lyse autologous and allogeneic MSCs. The activating NK receptors NKp30, NKG2D, and DNAM-1 represented the major receptors responsible for the induction of NK-mediated cytotoxicity against MSCs. Accordingly, MSCs expressed the known ligands for these activating NK receptors—ULBPs, PVR, and Nectin-2. Moreover, NK-mediated lysis was inhibited when IFN-γ-exposed MSCs were used as target cells as a consequence of the up-regulation of HLA class I molecules at the MSC surface. The interaction between NK cells and MSCs resulted not only in the lysis of MSCs but also in cytokine production by NK cells. These results should be taken into account when evaluating the possible use of MSCs in novel therapeutic strategies designed to improve engraftment or to suppress graft-versus-host disease (GVHD) in bone marrow transplantation.
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Grzywacz, Bartosz J., Nandini Kataria, Jeffrey S. Miller, and Michael R. Verneris. "Stromal Cells Support a Myeloid Pathway of Human NK Cell Differentiation." Blood 110, no. 11 (November 16, 2007): 1336. http://dx.doi.org/10.1182/blood.v110.11.1336.1336.
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Abstract Natural killer (NK) cells belong to the lymphocyte lineage; however a myeloid origin has been debated in the past based on nascent experimental evidence. We studied the in vitro development of human NK cells from UCB-derived CD34+ cells following culture with cytokines (IL15, IL7, SCF, FLT3L, IL3) on a murine fetal stromal cell line EL08.1D2 (Blood, 2006; 108: 3824–3833). We investigated the differential requirement of CD34+ subsets for stromal cell support. Limiting dilution experiments showed that CD34+ cells negative for phenotypic markers of NK commitment (CD7, CD161, integrin B7, CD122, CD45RA) absolutely require stromal cells and/or addition of hydrocortisone (HC) to differentiate into functional NK cells. Without stromal cells or HC those progenitors give rise to myeloid lineage cells, but not NK cells. Thus, we hypothesized that stromal cells could instruct myeloid precursors to convert to the NK lineage. Indeed, CD56+ cells generated in stroma supported cultures frequently co-express CD33 and CD13. To determine whether myeloid cells developing from CD34+ cells after 2–3 wk cultures could give rise to NK cells, we FACS sorted the CD56−CD33+CD13high and CD56−CD14+ populations. Such CD33+CD13high and CD14+ cells express macrosialin (CD68) and acquire lyzozyme (by FACS), confirming their myeloid characteristics. Sorted cells cultured further in cytokines alone (IL15, IL7, SCF, FLT3L) did not give rise to NK cells. However, in the presence of cytokines, stromal cells and HC, NK cells were generated. To exclude the possibility of NK cell contamination, CD33+CD13high and CD14+ cells were isolated from cultures of CD34+ cells in conditions not supportive of NK cell development (GM-CSF, IL3, FLT3L, SCF, without stroma, IL15 or IL7). Such cells gave the same results as above (i.e., NK cells developed only with stroma and HC). In additional studies, a fraction (∼16%) of CFU-GM colonies isolated from methylocellulose cultures could generate NK cells only in the presence of stromal cells, HC and cytokines, but not cytokines alone. As more of a definitive marker of the monocytic lineage, we used the surface expression of M-CSF receptor (CD115) on hematopoietic precursors. CD56−CD117+CD115+ and CD56−CD117+CD115− fractions were FACS sorted from 2–3 wk cultures of CD34+ cells. While both populations could differentiate into NK cells, only the CD115+ monocytic precursors required stromal cells. Quantitatively the CD117+CD115− cells were the main source of NK cells in this culture system. Notably the NK cells derived from CD115+ precursors were remarkably different, showing significantly higher expression of Killer Immunoglobulin-like Receptors (KIR: CD158a, CD158b and CD158e) than their CD115− derived counterparts (52% vs 15% KIR+, n=3, p=0.002). With respect to the repertoire of HLA-specific inhibitory receptors, NK cells derived from monocytic precursors resemble the dominant fraction of peripheral blood NK cells, including potentially alloreactive NK cells (KIR+CD94/NKG2A−). Collectively we present evidence that NK cells can be derived from developmental intermediates of the monocytic lineage and this differentiation pathway is dependent upon interaction with stroma. Our data indicate that the developmental trajectory shapes the pattern of inhibitory receptor expression on mature NK cells. Such findings have bearing on our understanding of NK cell biology, post transplant NK cell reconstitution and could explain the paucity of recognized immature NK cell leukemias coinciding with the occurrence of AML variants with NK specific antigen expression.
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Figueiredo-Pontes, Lorena Lobo, Robert S. Welner, Miroslava Kardosova, Hong Zhang, Meritxell Alberich-Jorda, and Daniel G. Tenen. "Cytokine-Mediated Natural Killer Cells Effects Impair Hematopoietic Stem Cell Function." Blood 128, no. 22 (December 2, 2016): 2641. http://dx.doi.org/10.1182/blood.v128.22.2641.2641.
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Abstract Natural killer (NK) cells participate in innate and adaptive immune responses, and upon activation rapidly produce cytokines, chemokines, and growth factors, including IFNγ, TNFα, TGFβ, GM-CSF, MIP1α, MIP1β, IL-10, and others, which can affect the function of other hematopoietic cells. Considering the recent evidences that hematopoietic stem cells (HSCs) respond to cytokine signaling, we hypothesized that NK cell-mediated cytokine production could mediate HSC function. By the use of co-cultures of purified Ly5.1 murine NK cells and congenic Ly5.2 HSCs, we concluded that NK activity affects HSC frequency in vitro as well as hematopoietic reconstitution in vivo. Sorted NK cells (CD3- NK1.1+) and HSCs (Lin-, Sca1+, ckithi, CD48-, CD150+) were co-cultured in the presence or absence of IL2 over an OP9 stromal cells layer for 14 to 28 days. After 14 days, the addition of NK cells to HSC cultures resulted in an approximate 2-fold reduction of lineage negative cells (Lin-) recovered cells, as compared to control HSC cultures, as determined by flow cytometry analysis. Lin- counts were even lower in HSC+NK long-term cultures when compared to HSC only cultures. Ly5.1 HSCs and/or Ly5.2 NK cells were injected into sublethally irradiated Ly5.1/2 chimeric mice in a ratio of 105 NK to 103 HSCs per mouse. The addition of IL2-stimulated NK to injected HSCs reduced engraftment from 15.7% to 1.82% when the 16 weeks bone marrow (BM) chimerism was analyzed. In agreement, donor CD45.1 cells contribution to the LSK and HSC subpopulations was reduced in the HSC+NK transplanted mice. To test whether NK depletion from BM grafts would affect HSC function, we performed limiting dilution transplantation assays where whole BM from Ly5.2 mice was submitted to immunonagnetic NK1.1 or IgG depletion and injected into lethally irradiated Ly5.1 animals. Donor chimerism after 8 and 16 weeks of transplant showed that depleting NK cells improves the engraftment ability of HSC in a cell dose-dependent manner. When 25 x104 BM cells were injected, chimerism increased from 40 to more than 90% in NK depleted group. Of note, HSC frequency was 1 in 1595 in the control and 1 in 95 in the NK depleted group. In order to understand the mechanisms by which NK cells could regulate HSCs, we took advantage of a CCAAT/enhancer-binding protein gamma (C/ebpg) knockout (KO) conditional mouse model generated in our laboratory, considering that C/ebpg had been previously shown to regulate NK cytotoxicity. Using similar culture conditions, HSCs and NK cells isolated from control (CT) or Cebpg KO mice were injected into congenic sublethally irradiated recipients. Results showed that Cebpg-deficient NK cells do not harm HSC engraftment as CT NK cells do. For instance, after 8 weeks, the addition of CT non-stimulated and IL-2-stimulated NK cells to normal transplanted HSCs reduced the engraftment from 40% to 20% and 10%, respectively. In contrast, chimerism was not different when HSCs only or HSCs + stimulated KO NK cells were transplanted. Gene expression and cytokine profiles of deficient and normal NK cells revealed the potential players of this HSC-NK regulation. Of these, interferon gamma (IFNg), was lower produced by the C/ebpg deficient NK cells. Therefore, besides controlling NK cytotoxicity, we showed here that C/ebpg also plays a role in the regulation of HSCs by NK-mediated cytokine production. Next, we investigated whether depletion of NK cells from human BM samples would improve transplantation efficiency. NK cells were removed using CD56 antibody and transplanted into sublethally irradiated NSG mice. Sixteen weeks after transplantation, animals were sacrificed and the percentage of human CD45 cells in blood, BM, and spleen demonstrated that NK depletion from human BM favors engraftment. Altogether, these findings provide new insights to the knowledge of HSC regulation by NK cells, which are present in BM transplantation (BMT) grafts. Although the alloreactive effect of NK cells against non-identical tumor cells from BMT recipients is well known, its cytokine-mediated effects over identical progenitor cells from the graft were not previously explored. We show that NK-secreted cytokines harm stem cell function, thus suggesting that depletion of NK cells from BM donor cells preparations can improve stem cell engraftment, particularly in the setting of alternative transplants with limiting cell numbers or non-myeloablative conditioning regimens. Disclosures No relevant conflicts of interest to declare.
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Velasquez, Mireya Paulina, Arpad Szoor, Challice L. Bonifant, Abishek Vaidya, Lorenzo Brunetti, Michael C. Gundry, Robin Parihar, Margaret Goodell, and Stephen Gottschalk. "Two-Pronged Cell Therapy for B-Cell Malignancies: Engineering NK Cells to Target CD22 and Redirect Bystander T Cells to CD19." Blood 128, no. 22 (December 2, 2016): 4560. http://dx.doi.org/10.1182/blood.v128.22.4560.4560.
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Abstract Background: T-cell therapy with CD19-CAR T cells has been very successful for the treatment of B-cell derived malignancies in humans. However, cytokine release syndrome, neurotoxicity, and development of CD19- escape variants have emerged as potential limitations. Developing CAR NK-cell based therapies might overcome some of these side effects since NK cells do not rapidly expand or persist long-term after adoptive transfer. However, CAR NK-cell therapies are less effective than CAR T-cell therapies in preclinical models. To overcome these limitations we have devised a strategy to genetically modify NK cells with CD22-CARs and CD19/CD3-bispecific T-cell engager (CD19-ENG) molecules. These NK cells should not only kill CD22+ B cells directly, but also redirect bystander T cells to malignant CD19+ B cells, enhancing antitumor effects and preventing immune escape. Methods: NK cells were generated using K562s expressing 41BBL and membrane bound IL15, and genetically modified with a retroviral vector encoding a CD22-CAR with a 41BB.ζ endodomain and/or a retroviral vector encoding CD19-ENG and mOrange separated by an IRES. To mimic immune escape, CD19 or CD22 knockout (ko) Ph+ leukemia cells (BV173) were generated by CRISPR/cas9. The effector function of genetically modified NK cells was evaluated using standard immunological assays. Results: After transduction 70-80% of NK cells expressed CD22-CARs, and ~50% expressed CD22-CARs and CD19-ENGs as judged by FACS analysis. We performed coculture and cytotoxicity assays using non-transduced (NT), CD22-CAR, CD19-ENG, and CD22-CAR/CD19-ENG NK cells as effectors and BV173 (CD19+/CD22+), BV173.koCD19, BV173.koCD22, Daudi (CD19+/CD22+), and KG1a (CD19-,CD22-) as targets. Cocultures were preformed +/- T cells and after 24 hours IFNγ and IL2 was determined by ELISA. In the absence of T cells, CD22-CAR and CD22-CAR/CD19-ENG NK cells only recognized CD22+ targets as judged by IFNγ production. Moreover, CD22-CAR/CD19-ENG and CD19-ENG NK cells efficiently redirected T cells to secrete IFNγ in the presence of CD19+/CD22- targets. No NK-cell population produced IL2, however CD22-CAR/CD19-ENG and CD19-ENG NK cells induced IL2 production of T cells in the presence of CD19+ targets. No significant cytokine production was observed in the absence of antigen (media, KG1a). Specificity of generated NK cells was confirmed in cytotoxicity assays. In vivo studies to confirm our in vitro findings are in progress. Conclusions: We have generated for the first time NK cells that kill B-cell malignancies through a CAR (CD22) and simultaneously redirect bystander T cells to a 2nd B-cell antigen (CD19) to enhance antitumor effects and prevent immune escape. Genetic modification of NK cells to enhance their antitumor activity and redirect bystander T cells may present a promising addition to current cell therapies for B-cell malignancies. Disclosures No relevant conflicts of interest to declare.
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Butler, Noah S., and John T. Harty. "A “memorable” NK cell discovery." Cell Research 19, no. 3 (March 2009): 277–78. http://dx.doi.org/10.1038/cr.2009.23.
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Batista, Inês A., Sofia T. Quintas, and Sónia A. Melo. "The Interplay of Exosomes and NK Cells in Cancer Biology." Cancers 13, no. 3 (January 26, 2021): 473. http://dx.doi.org/10.3390/cancers13030473.
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Natural killer (NK) cells are innate lymphoid cells involved in tumor surveillance. These immune cells have the potential to fight cancer growth and metastasis, as such, their deregulation can result in tumor immune escape. Recently exosomes were described as mediators of intercellular communication between cancer and NK cells. The exact role of this subclass of extracellular vesicles (EVs), which transport genetic and molecular material to recipient cells, in NK cell biology in the context of cancer, is still an open question. Several reports have demonstrated that tumor-derived exosomes (TDEs) can exert immunomodulatory activities, including immunosuppression, thus promoting cancer progression. Some reports demonstrate that the interplay between cancer exosomes and NK cells allows tumors to escape immune regulation. On the other hand, tumor exosomes were also described to activate NK cells. Additionally, studies show that NK cell exosomes can modulate the immune system, opening up their potential as an immunotherapeutic strategy for cancer treatment. Our review will focus on the reprogramming effect of cancer exosomes on NK cells, and the immunotherapeutic potential of NK cells-derived exosomes.
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Uherek, Christoph, Torsten Tonn, Barbara Uherek, Sven Becker, Barbara Schnierle, Hans-Georg Klingemann, and Winfried Wels. "Retargeting of natural killer–cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction." Blood 100, no. 4 (August 15, 2002): 1265–73. http://dx.doi.org/10.1182/blood.v100.4.1265.h81602001265_1265_1273.
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The continuously growing natural killer (NK) cell line NK-92 is highly cytotoxic against malignant cells of various origins without affecting normal human cells. Based on this selectivity, the potential of NK-92 cells for adoptive therapy is currently being investigated in phase I clinical studies. To further enhance the antitumoral activity of NK-92 cells and expand the range of tumor entities suitable for NK-92–based therapies, here by transduction with a retroviral vector we have generated genetically modified NK-92 cells expressing a chimeric antigen receptor specific for the tumor-associated ErbB2 (HER2/neu) antigen, which is overexpressed by many tumors of epithelial origin. The chimeric antigen receptor consists of the ErbB2-specific scFv(FRP5) antibody fragment, a flexible hinge region derived from CD8, and transmembrane and intracellular regions of the CD3 ζ chain. Transduced NK-92-scFv(FRP5)-ζ cells express high levels of the fusion protein on the cell surface as determined by fluorescence-activated cell-scanning (FACS) analysis. In europium release assays, no difference in cytotoxic activity of NK-92 and NK-92-scFv(FRP5)-ζ cells toward ErbB2-negative targets was found. However, even at low effector-to-target ratios, NK-92-scFv(FRP5)-ζ cells specifically and efficiently lysed established and primary ErbB2-expressing tumor cells that were completely resistant to cytolytic activity of parental NK-92 cells. These results demonstrate that efficient retargeting of NK-92 cytotoxicity can be achieved and might allow the generation of potent cell-based therapeutics for the treatment of ErbB2-expressing malignancies.
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Kaufman, Dan S. "Human Pluripotent Stem Cell-Derived Blood Cells for Therapies." Blood 132, Supplement 1 (November 29, 2018): SCI—14—SCI—14. http://dx.doi.org/10.1182/blood-2018-99-109424.
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Abstract It has now been twenty years since human embryonic stem cells (hESCs) were first isolated and described in 1998. In the next decade, induced pluripotent stem cells (iPSCs) were produced first from mouse somatic cells and then from human cells. Since these landmark advances, hESCs and iPSCs have been utilized to advance our understanding of basic human developmental biology and cellular plasticity. These lessons are crucial to fulfill the goal to use human pluripotent stem cells to derive new cellular therapies to better treat and repair organs and tissues damaged by disease, trauma or aging. Clinical trials are underway to utilize differentiated cells derived from hESCs or iPSCs for treatment of retinal disease, spinal cord injury, diabetes, cardiac failure, and other disorders. Production of therapeutic blood cells such as transplantable hematopoietic stem cells (HSCs) from hESCs and iPSCs remains a key goal. However, despite intensive research efforts by our group and many others, there remain challenging to achieve long-term multi-lineage engraftment in vivo with HSCs derived from unmodified hESCs/iPSCs. More successful approaches have used genetic modification or teratoma formation, though these strategies cannot be directly translated to clinical cell products. Reasons for this continued challenge and novel solutions such as use of a Runx1 genetic reporter system will be discussed. In contrast to production of transplantable HSCs, the ability use hESCs/iPSCs to produce functional lymphocytes with anti-tumor and anti-viral activity has been quite successful. Our group has defined methods to efficiently differentiate and expand clinical-scale quantities of natural killer (NK) cells. These hESC/iPSC-derived NK cells have phenotypic and genetic profiles similar to NK cells isolated from peripheral blood. Additionally, hESC/iPSC-derived NK cells are able to kill diverse tumor cells in vitro and in vivo. The hESCs/iPSCs also serve as a versatile platform to engineer genetic enhancements to produce NK cells with improved anti-tumor activity. For example, we have produced hESC/iPSC-derived NK cells that express novel chimeric antigen receptors (CARs) that are able to better target tumors that are more refractory to NK cell-mediated killing. This optimized NK-CAR construct utilizes the NKG2D transmembrane domain, 2B4 co-stimulatory domain, and the CD3ζ signaling domain to activate key NK cell-specific intracellular signaling pathways and increase NK cell survival and expansion in vivo. In one direct comparison between CAR-expressing-iPSC-derived NK cells and "conventional" CAR-expressing T cells, demonstrates the CAR-NK cells have similar ability to kill ovarian tumors in vivo, but with less toxicity, suggesting a safer approach. We have engineered other modifications into iPSC-NK cells to enhance NK cell targeting, proliferation, expansion and survival -- all key qualities to improve in vivo anti-tumor activity. These studies demonstrate that hESC/iPSC-provide an ideal platform to produce standardized, targeted, "off-the-shelf" cellular immunotherapies to treat refractory hematological malignancies and solid tumors. Finally, iPSC-derived NK cells are now being produced at clinical scale under current good manufacturing practices (cGMP) conditions with clinical trials scheduled to start by the end of 2018. Disclosures Kaufman: Fate Therapeutics: Consultancy, Research Funding.
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Tsujimoto, Hironori, Takefumi Uchida, Philip A. Efron, Philip O. Scumpia, Amrisha Verma, Tadashi Matsumoto, Sven K. Tschoeke, et al. "Flagellin enhances NK cell proliferation and activation directly and through dendritic cell-NK cell interactions." Journal of Leukocyte Biology 78, no. 4 (July 20, 2005): 888–97. http://dx.doi.org/10.1189/jlb.0105051.
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Li, Li, Muharrem Muftuoglu, Han Chen, Duncan Mak, Elif Gokdemir, Hila Shaim, Jared Burks, et al. "Cytomegalovirus Reactivation Shapes NK Cells Diversity Following Allogeneic Hematopoietic Stem Cell Transplantation." Blood 128, no. 22 (December 2, 2016): 4588. http://dx.doi.org/10.1182/blood.v128.22.4588.4588.
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Abstract Natural killer (NK) cells are the first lymphocyte population to reconstitute following allogeneic hematopoietic stem cell transplantation (HSCT) and are key players in immune defense against viral infections and malignant transformation. NK cell numbers generally recover within the first month post-transplant, but the acquisition of mature NK cell phenotype and full functional competency can take over 6 months and is influenced by various host and donor factors. Cytomegalovirus (CMV) infection has been shown to modulate NK cell maturation after HSCT. The diversity of the NK cell repertoire is dictated by a variety of combinatorially expressed activating and inhibitory receptors that dictate the NK activation status. Moreover, whereas the expression of inhibitory receptors is primarily genetically determined, environmental factors such as viral infections influence the expression of activating receptors to a great extent.. We propose that assessment of diversity could provide a different perspective for the evaluation of the NK cell compartment after HSCT, since it is a quantitative measure that takes into account both the number and evenness of the different NK subpopulations. To better understand the factors that influence NK cell recovery after cord blood (CB) transplant (CBT) and specifically the influence of cytomegalovirus (CMV) infection on NK cell maturity, we used 40-parameter mass cytometry (CyTOF) to interrogate the NK cell repertoire. A panel including 37 monoclonal antibodies was designed to recognize NK cells lineage markers and receptors as well as intracellular markers such as transcription factors and adaptor proteins. We first evaluated and compared the diversity of NK cells in 10 CB units and peripheral blood (PB) from 20 healthy donors. We then examined the diversity of NK cells before and after CBT in 22 serially collected blood samples from in 10 CBT recipients. NK cell diversity was significantly lower in CB (mean 574, range 417-891) compared to PB samples from healthy donors (mean 3792, range 1284-5079; P=0.001), indicating less diversification within the naive CB NK compartment. After CBT, NK cell diversity was lower at earlier time point (Day30) (mean 1129, range 428-1768) compared to PB from healthy donors; P=0.01. The diversity of NK cells increased gradually over time following CBT (Day 30 mean 1129 range 428-1768; Day 60, mean 1185, range 515-1864; 4 months, mean 1711 range 597-2640). We also compared the diversity of NK cells in the PB of healthy CMV seronegative (n=10) and seropositive adult donors (n=10). The diversity of NK cells was higher in CMV seropositive vs. CMV seronegative healthy donors (3887 vs 2473; P=0.04). This difference in NK diversity was even more pronounced within the KIR positive (mean 1701, range, 981-2152) compared to the KIR negative subset (mean 551, range 456-647; P=0.02), indicating that CMV infection increases the richness of mature NK cells. In keeping with these findings, CMV infection after CBT was associated with a significantly greater diversity of NK cells, especially within the KIR positive compartment (mean 604, range 207-1035) compared to the KIR negative subset (mean 283, 257-457; P=0.025). However, in CMV negative patients, we found no difference in diversity within the KIR positive and negative subsets (mean 1120 vs. 1366; P=0.28). Taken together, these data suggest that NK cell diversity reflects NK cells differentiation and maturation, and that CMV shapes NK cell diversity, especially within the KIR positive compartment. To further understand how CMV influences NK cells diversity, we examined the top 15 NK cell subsets and their distribution at multiple timepoints before and after CMV reactivation post-CBT. CMV infection post-CBT was associated with a significant change in the distribution of NK subsets within the KIR positive population, with the top 15 subsets prior to CMV reactivation being mostly replaced by the emergence of new subsets. In contrast, the top 15 subsets within the KIR negative NK population remained stable. These data suggest that CMV drives NK cell maturation by differentiating KIR positive NK cells. In summary, we used high-dimensional single-cell data to evaluate NK cell reconstitution following HSCT. These data can help us better understand the biology of NK cell recovery after HSCT and discover the functional significance of NK cell diversity in the setting of viral infections. Disclosures Champlin: Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.
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Bos, Gerard M. J., Janine CHMJ Van Elssen, Joris Vanderlocht, Brigitte LMG Senden-Gijsbers, and Wilfred LMG Germeraad. "Role of Human NK Cells in Dentric-Cell Based Vaccine." Blood 112, no. 11 (November 16, 2008): 1550. http://dx.doi.org/10.1182/blood.v112.11.1550.1550.
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Abstract Figure Figure Besides their prominent role in the destruction of altered self-cells, natural killer (NK) cells have been shown to potentiate T cell responses by interacting with dendritic cells (DC). In mouse models as well as in a recent human study it has been demonstrated that DC might activate NK cells. In the context of dendritic cell-based vaccines – i.e. optimising the optimal maturation cocktail - it remains to be determined if and how NK-DC interactions depend on differential DC maturation and what factors influence the NK activation.. By comparing differential DC differentiation (IL-4/GM-CSF and IL-13/GMCSF) and maturation cocktails (IFN-γ/FMKp and PGE2/TNF-α), we show that the ability of human DCs to attract NK cells is imprinted during DC maturation. Only FMKP/IFN-γ (stimulation Toll like receptor 2 and 4) maturated DCs have the capacity to actively recruit NK cells in vitro and our data indicate that CCR5 is the dominant chemokine receptor in this recruitment (Figure 1). Furthermore, in contrast to PGE2/TNF-α matured DC, FMKP/IFN-γ maturated DCs activate NK cells to produce IFN-γ in a IL-12/IL18 dependent manner, of which we show it contributes to strong TH1 polarization. In addition upon contact with these DCs NK cells upregulate their lymph node homing receptors, possibly inducing secondary migration to the lymph nodes. In conclusion, besides the identification of a superior DC maturation cocktail which contributes to NK-DC interactions, we identified a novel recruitment mechanism for peripheral human NK cells which may contribute to secondary, central DC-NK interactions and strong TH1 polarization.
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Murphy, William J., Isabel Bareo, Alan M. Hanash, Lisbeth A. Welniak, Kai Sun, Bruce R. Blazar, and Robert B. Levy. "Suppression of NK Cell-Mediated Bone Marrow Cell Rejection by CD4+CD25+ Regulatory T Cells: Linkage of Adaptive to Innate Responses." Blood 106, no. 11 (November 16, 2005): 2195. http://dx.doi.org/10.1182/blood.v106.11.2195.2195.
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Abstract While a link between the innate to adaptive immune system has been established, studies demonstrating direct effects of T cells in regulating Natural Killer (NK) cell function have been lacking. Naturally occurring CD4+CD25+ regulatory T cells (Tregs) have been shown to potently inhibit adaptive responses by T cells. We therefore investigated whether Tregs could affect NK cell function in vivo. Using a bone marrow transplantation (BMT) model of hybrid resistance, in which parental (H2d) marrow grafts are rejected by the NK cells of the F1 recipients (H2bxd), we demonstrate that the in vivo removal of host Tregs significantly enhances NK-cell mediated BM rejection. This heightened rejection was mediated by the specific NK cell Ly-49+ subset previously demonstrated to reject the BMC in this donor/host pairing. The depletion of Tregs could also further increase rejection already enhanced by treating recipients with the NK cell activator, poly I:C. Although splenic NK cell numbers were not significantly altered, increased splenic NK in vitro cytotoxic activity was observed from the recovered cells. The regulatory role of Tregs was confirmed in adoptive transfer studies in which transferred CD4+CD25+ Tregs resulted in abrogation of NK cell-mediated hybrid resistance. Thus, Tregs can potently inhibit NK cell function in vivo and their depletion may have therapeutic ramifications with NK cell function in BMT and cancer therapy.
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Velardi, Andrea. "NK cell adoptive immunotherapy." Blood 105, no. 8 (April 15, 2005): 3006. http://dx.doi.org/10.1182/blood-2005-01-0322.
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Suck, Garnet, Donald R. Branch, Joanna Vergidis, Soad Fahim, and Armand Keating. "Identifying Mechanisms of Enhanced NK Cell Cytotoxicity Using Permanent NK Cell Lines." Blood 104, no. 11 (November 16, 2004): 3842. http://dx.doi.org/10.1182/blood.v104.11.3842.3842.
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Abstract Although NK cells are promising candidates for adoptive immunotherapy and at least one permanent cell line is in clinical trials, further studies evaluating efficacy and mechanisms of action are warranted. As a first step towards identifying the most potent effector cells, we investigated the molecular mechanisms of cytotoxicity of the three natural killer lines, KHYG-1, NK-92 and YT, and the NK-T cell line, SNT-8, under standardized culture conditions with human serum as the only serum source. We confirmed the previously established differential killing potential of the 4 cell lines against target K562 cells using a new method based on detecting Annexin V (+) target cells by flow cytometry. By labeling the NK cells with specific antibodies, the assay is designed to screen any target cell for NK cytotoxicity. In contrast to previous reports, we found KHYG-1 the most cytotoxic, followed by NK-92, SNT-8 and YT. Genotypic and transcriptional phenotypic analysis of the cell lines for killer cell Ig-like receptors (KIRs) by SSP-PCR showed that inhibitory KIRs outnumbered activating KIRs in all cases but did not explain the differential cytotoxicity. A correlation with cytotoxicity was found with expression of the activating type II C lectin-like receptor, NKG2D: KHYG-1, 99%+; NK-92, 91%+; SNT-8, 6%+ and YT, 2%+. Moreover, the ITAM-bearing adaptor molecule DAP12, involved in the alternative activation signaling pathway via NKG2C-CD94 and activating KIRs, was detected only for KHYG-1 by immunoblotting, These data suggest that the superior cytotoxicity of KHYG-1 may be due, in part, to the additional activation of this alternative pathway that is not triggered in the other lines. The downstream signaling molecules involved in NK cytotoxicity, including the tyrosine phosphatases SHP-1, SHP-2 and SHIP-1 (inhibitory), as well as SHIP-2, the tyrosine kinases ZAP-70, Syk, PI3K and the MAP kinase phospho-ERK-2 (activating) were compared among the lines by immunoblotting followed by densitometry normalized to b-actin or ERK-2 for phospho-ERK-2. We found that the activating kinase Syk was expressed only in NK-92 and KHYG-1 at even higher levels. Also, phospho-ERK-2, was hyperphosphorylated only in KHYG-1. Perforin, granzyme A and granzyme B, present in cytotoxic granules, were compared by RT-PCR and intracellular flow cytometry and/or immunoblotting. Perforin was found to be almost exclusively fully processed to the active 60 kD form only in KHYG-1, in contrast to the other lines, which displayed approximately half the levels of the active form. These data provide a further explanation for the superior cytotoxicity of KHYG-1 and demonstrate the value of comparing cell lines with diverse cytotoxic potential as a means of elucidating cell killing mechanisms. It is conceivable that targeted modifications to the signaling pathways for cytotoxicity in this model will lead to the generation of activated NK cells with even greater efficacy.
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Luo, Dian Zhong. "On the cell biology of pit cells, the liver-specific NK cells." World Journal of Gastroenterology 6, no. 1 (2000): 1. http://dx.doi.org/10.3748/wjg.v6.i1.1.
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Wang, Zhe. "NK cell-regulated tumour dormancy." Nature Cell Biology 23, no. 7 (July 2021): 677. http://dx.doi.org/10.1038/s41556-021-00714-w.
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Isgro, Antonella, Marco Marziali, Pietro Sodani, Javid Gaziev, Paola Polchi, Gioia De Angelis, Daniela Fraboni, Wilma Leti, Fernando Aiuti, and Guido Lucarelli. "Donor’s NK Cells May Influence the Engraftment in Pediatrics Patients after T-Cell Depleted Haploidentical Stem Cell Transplant for Thalassemia." Blood 112, no. 11 (November 16, 2008): 4595. http://dx.doi.org/10.1182/blood.v112.11.4595.4595.
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Abstract In haploidentical hematopoietic transplantation, donor-versus-recipient NK cell alloreactivity derives from a mismatch between donor NK clones bearing inhibitory Killer Cell Ig-like Receptors (KIRs) for self HLA class I molecules and their HLA class I ligands (KIR ligands) on recipient cells. The mechanism whereby alloreactive NK cells exert their benefits in transplantation has been elucidated. The infusion of alloreactive NK cells ablates recipient T cells which reject the graft, and ablates recipient dendritic cells (DCs) which trigger GvHD, thus protecting from GvHD (Ruggeri et al., Science 2002). NK cell alloreactivity also boosts very rapid rebuilding of donor adaptive immunity to infections. In this study we analysed the potential role of NK cells after haploidentical transplant in b-thalassemia patients. T and B cell depletion was carried out with CD34+ coated magnetic microbeads and the CliniMACS device (Miltenyi Biotec©) from peripheral blood and bone marrow of donors (the mothers) and resulted in grafts consisting of stem cells and effector cells (NK cells, monocytes) with the addition of bone marrow mononuclear cells (BMMNCs 3 × 105/kg of the recipient). A total of 11 pediatric patients with b-thalassemia received T and B cell depleted transplants from their haploidentical mothers with a median number of 15 ×106 CD34 stem cells. To analyse the mechanisms involved in immunological reconstitution post transplant, we analysed T cell subsets by flow cytometry, particularly NK sets (CD3- CD56+, CD3− CD16+ and CD56+CD16+ NK cells) at day + 20 and + 60 post transplant. Day + 20 post transplant, the patients had significantly lower CD4+ T cells in comparison to the controls (1.9 ± 1.4% vs. 47.5 ± 6% respectively), whereas CD8+ T cells numbers did not statistically differ between patients and controls (24.2 ± 33.7% vs. 20 ± 7%). NK cells were among the first lymphocytes to repopulate the peripheral blood, and up to 70% of these cells were CD3-CD56+bright cells. Interestingly, a direct correlation has been observed between the percentages of CD56+CD16+ NK subset and the BM engraftment (in mean 71 ± 21% CD56+CD16+ in the four patients with full engraftment, 27 ± 28% in the three patients with a stable mixed chimerism after BM transplant (70–80% of donor cells) and 1.4 ± 1% in the four patients with rejection). In all the patients the origin of the NK subsets was from the mothers. Day + 60 post transplant an increase in the percentages of CD4+ T cells, naïve CD4+ cells and in thymic naïve Th cells were observed (3 ± 1.2%, 2.9 ± 2.1%, 2.7 ± 1%, respectively). CD8+ T cells were also increased (in mean 35 ± 27.5%), in parallel with the increase of the CD3-CD16+ NK cells (potent cytotoxic effector cells) especially in the patients with full engraftment (in mean 47 ± 20% vs. 28 ± 31% in mixed chimerism) NK CD56+bright cells develop more rapidly than other lymphocytes, but CD16+ NK cells (with cytotoxic potential) require more prolonged exposure to maturation factor (IL-2) in the bone marrow. Interestingly we observed higher percentages of NK subsets just twenty days post transplant in the patients with full engraftment respect the mixed chimerism and the rejection, suggesting a role of donor NK cells on improved engraftment and on prevention of the rejection with the attack of the host lympho-hematopoietic cells. These observations may suggest the importance of NK subsets analyses at the first time of the transplant as an useful parameter for the outcome of the transplant and/or the use of donor’s alloreactive NK cells especially in haploidentical recipients.
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Guo, Shuwei, Chao Huang, Fengfeng Han, Bin Chen, Ying Ding, Yuanyuan Zhao, Zhihong Chen, et al. "Gastric Cancer Mesenchymal Stem Cells Inhibit NK Cell Function through mTOR Signalling to Promote Tumour Growth." Stem Cells International 2021 (June 29, 2021): 1–17. http://dx.doi.org/10.1155/2021/9989790.
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The dysfunction of natural killer (NK) cells has been increasingly reported in malignancies, especially in solid tumours. Mesenchymal stem cells (MSCs) exhibit pleiotropic functions that include mediating immune cell exhaustion which is implicated in cancer progression. However, the association of MSCs derived from gastric cancer (gastric cancer mesenchymal stem cells: GCMSCs) with the dysfunction of NK cells remains poorly understood. In this study, we demonstrated that GCMSCs effectively contributed to the exhaustion of NK cells through the release of soluble factors. Furthermore, passivation of the antitumour effect in NK cells was closely associated with their dysfunctional state. The GCMSC-conditioned medium prevented the frequency and effector function of infiltrating NK cells in tumour-bearing mouse models, thus promoting tumour growth. Mechanistically, mammalian target of rapamycin (mTOR) signalling, a critical regulator of cellular metabolism that mediates the function of immune cells, was inhibited in NK cells treated with GCMSCs. However, the checkpoint receptor PD-1 was still present at minimal levels with or without GCMSCs. The study results revealed that GCMSCs contributed to dysfunctional NK cells involved at least partially in the inhibition of mTOR signalling, suggesting potential directions for NK cell-based cancer immunotherapy.
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Reiners, Katrin S., Daniela Topolar, Alexander Henke, Venkateswara R. Simhadri, Jörg Kessler, Maike Sauer, Martina Bessler, et al. "Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity." Blood 121, no. 18 (May 2, 2013): 3658–65. http://dx.doi.org/10.1182/blood-2013-01-476606.
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Key Points Exosomal NKp30-ligand BAG6 is crucial for detection of tumor cells by NK cells in vitro and in vivo. Soluble plasma factors including BAG6 suppress NK cell cytotoxicity and promote evasion of CLL cells from NK cell anti-tumor activity.
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Elewaut, Dirk, and Mitchell Kronenberg. "Molecular biology of NK T cell specificity and development." Seminars in Immunology 12, no. 6 (December 2000): 561–68. http://dx.doi.org/10.1006/smim.2000.0275.
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Ndhlovu, Lishomwa C., Sandra Lopez-Vergès, Jason D. Barbour, R. Brad Jones, Aashish R. Jha, Brian R. Long, Eric C. Schoeffler, Tsuyoshi Fujita, Douglas F. Nixon, and Lewis L. Lanier. "Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity." Blood 119, no. 16 (April 19, 2012): 3734–43. http://dx.doi.org/10.1182/blood-2011-11-392951.
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Abstract Natural killer (NK) cells are innate lymphocytes that play an important role against viral infections and cancer. This effect is achieved through a complex mosaic of inhibitory and activating receptors expressed by NK cells that ultimately determine the magnitude of the NK-cell response. The T-cell immunoglobulin– and mucin domain–containing (Tim)–3 receptor was initially identified as a T-helper 1–specific type I membrane protein involved in regulating T-cell responses. Human NK cells transcribe the highest amounts of Tim-3 among lymphocytes. Tim-3 protein is expressed on essentially all mature CD56dimCD16+ NK cells and is expressed heterogeneously in the immature CD56brightCD16– NK-cell subset in blood from healthy adults and in cord blood. Tim-3 expression was induced on CD56brightCD16− NK cells after stimulation with IL-15 or IL-12 and IL-18 in vitro, suggesting that Tim-3 is a maturation marker on NK cells. Whereas Tim-3 has been used to identify dysfunctional T cells, NK cells expressing high amounts of Tim-3 are fully responsive with respect to cytokine production and cytotoxicity. However, when Tim-3 was cross-linked with antibodies it suppressed NK cell–mediated cytotoxicity. These findings suggest that NK-cell responses may be negatively regulated when NK cells encounter target cells expressing cognate ligands of Tim-3.
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Hurton, Lenka, R. Iram Siddik, Harjeet Singh, Simon Olivares, Brian Rabinovich, William Hildebrand, Dean Lee, et al. "Identifying NK-Cell Donors for Cell Therapy Based on Functional Phenotype." Blood 110, no. 11 (November 16, 2007): 3271. http://dx.doi.org/10.1182/blood.v110.11.3271.3271.
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Abstract Donor natural killer (NK) cells after haploidentical hematopoietic stem-cell transplantation (HSCT) and infusion of haploidentical NK-cells have demonstrated a therapeutic effect. NK alloreactivity resulting from appropriate Killer cell Ig-like receptor (KIR)-ligand disparity in human-leukocyte-antigen (HLA)-haplotype mismatched HSCT has resulted in improved engraftment and decreased incidence of leukemia relapse. Yet, not all patient-donor pairs benefit for an allogeneic NK-cell effect. To identify NK-cell donors with a suitable KIR-ligand mismatch, we have developed a functional assay to measure NK-cell killing through KIR-ligand interactions. NK-cell lysis of target cells is blocked by inhibitory KIR that recognize classical HLA class I allotypes and HLA mismatches of an altered allelic repertoire, as in haploidentical HSCT, leading to KIR-ligand mismatch and alloreactive NK cell-mediated target killing (Figure 1A). A cytotoxicity assay was developed based on the NK-cell target HLAnull 721.221 cells, and a panel of targets with enforced expression of HLA genes recognized by KIR. After the killing assay was optimized for high throughput and sensitivity, we used the panel of targets to determine whether bulk populations of donor NK cells could be predicted to kill based on KIR and HLA typing. The results demonstrate patterns of target-cell lysis for the KIR repertoires corresponding, for some donors, with predicted donor-versus-recipient NK-cell alloreactivity (Figure 1B). A relative inhibition of HLA+ target-cell lysis of >30% was associated with binding of KIR to introduced HLA class I molecules. The benefit of this assay to transplant physicians is a tool to actually measure phenotype (lysis), rather than relying on predictive models based on genotype. This assay will be combined with typing data to help identify donors with NK-cell killing function for recipients of haploidentical HSCT and infusion of haploidentical NK cells. Figure 1. (A) Schematic of alloreactivity generated between NK cells that are KIR-ligand mismatched with targets. (B) Observed lysis of 721.221 cells, with enforced expression of HLA class I, by KIR-typed donar(box). Figure 1. (A) Schematic of alloreactivity generated between NK cells that are KIR-ligand mismatched with targets. (B) Observed lysis of 721.221 cells, with enforced expression of HLA class I, by KIR-typed donar(box).
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Leong, Jeffrey W., Ryan P. Sullivan, and Todd A. Fehniger. "Natural Killer Cell Regulation by MicroRNAs in Health and Disease." Journal of Biomedicine and Biotechnology 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/632329.
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Natural killer (NK) cells are innate immune lymphocytes that are critical for normal host defense against infections and mediate antitumor immune responses. MicroRNAs (miRNAs) are a family of small, noncoding RNAs that posttranscriptionally regulate the majority of cellular processes and pathways. Our understanding of how miRNAs regulate NK cells biology is limited, but recent studies have provided novel insight into their expression by NK cells, and how they contribute to the regulation of NK cell development, maturation, survival, and effector function. Here, we review the expression of miRNAs by NK cells, their contribution to cell intrinsic and extrinsic control of NK cell development and effector response, and their dysregulation in NK cell malignancies.
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Belizário, José E., Jennifer M. Neyra, and Maria Fernanda Setúbal Destro Rodrigues. "When and how NK cell-induced programmed cell death benefits immunological protection against intracellular pathogen infection." Innate Immunity 24, no. 8 (September 20, 2018): 452–65. http://dx.doi.org/10.1177/1753425918800200.
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NK cells are innate lymphoid cells that exert a key role in immune surveillance through the recognition and elimination of transformed cells and viral, bacterial, and protozoan pathogen-infected cells without prior sensitization. Elucidating when and how NK cell-induced intracellular microbial cell death functions in the resolution of infection and host inflammation has been an important topic of investigation. NK cell activation requires the engagement of specific activating, co-stimulatory, and inhibitory receptors which control positively and negatively their differentiation, memory, and exhaustion. NK cells secrete diverse cytokines, including IFN-γ, TNF-α/β, CD95/FasL, and TRAIL, as well as cytoplasmic cytotoxic granules containing perforin, granulysin, and granzymes A and B. Paradoxically, NK cells also kill other immune cells like macrophages, dendritic cells, and hyper-activated T cells, thus turning off self-immune reactions. Here we first provide an overview of NK cell biology, and then we describe and discuss the life–death signals that connect the microbial pathogen sensors to the inflammasomes and finally to cell death signaling pathways. We focus on caspase-mediated cell death by apoptosis and pro-inflammatory and non-caspase-mediated cell death by necroptosis, as well as inflammasome- and caspase-mediated pyroptosis.
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Delfino, DV, KD Patrene, J. Lu, A. Deleo, R. Deleo, RB Herberman, and SS Boggs. "Natural killer cell precursors in the CD44neg/dim T-cell receptor population of mouse bone marrow." Blood 87, no. 6 (March 15, 1996): 2394–400. http://dx.doi.org/10.1182/blood.v87.6.2394.bloodjournal8762394.
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Natural killer (NK) cells develop from the nonadherent cell component of NK long-term bone marrow (BM) cultures (NK-LTBMC). Because these nonadherent cells are depleted of mature NK cells and T cells, but appear to enriched for NK precursors, they were used as a starting population to begin to define the NK precursors that function in NK- LTBMC. As the stromal cell component of NK-LTBMC has been shown to support interleukin (IL)-2-induced, CD44 dependent, NK cell development from nonadherent NK precursors, NK-LTBMC stroma was used in a limiting dilution assay (LDA) to quantitate the precursors. NK-LTBMC in 96-well plates were irradiated (20 Gy) to kill hematopoietic cells (including the NK precursors), seeded with limiting dilutions of the cells to be quantitated, cultured with 500 U/mL IL-2 for 13 days and assayed for development of NK activity by adding 51Cr-labeled YAC-1 cells to the wells and evaluating the release of 51Cr after 4 hours. Flow cytometric analysis, sorting, and quantitation of the nonadherent cell component of NK-LTBMC showed that NK precursors were concentrated in the CD44neg/dim subset that comprised 10% of the “lymphoid” gated cells. When the CD44neg/dim subset was sorted from BM of mice treated with 5- fluorouracil (5-FU) day before (-1FUBM), there were about 30% T cells, but no NK-1.1+ cells. When the T cells were removed by sorting and the CD44neg/dim, alphabeta, gammadelta T-cell receptorneg (TCR-) subpopulation was seeded onto irradiated stroma with IL-2, they proliferated, developed NK activity, became NK-1.1+ and CD44bright and remained alphabeta, gammadelta TCR-. The frequency of NK precursors in this population as estimated from the LDA was about 1/500.
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Taniguchi, Ruth T., Dustin Guzior, and Vinay Kumar. "2B4 inhibits NK-cell fratricide." Blood 110, no. 6 (September 15, 2007): 2020–23. http://dx.doi.org/10.1182/blood-2007-02-076927.
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Abstract 2B4 (CD244) and its ligand, CD48, are expressed on all natural killer (NK) cells. In studies using 2B4-deficient, CD48-deficient, or wild-type NK cells with blocking antibodies, we found that in the absence of 2B4-CD48 interactions, activated murine NK cells kill each other. We also show that NK-NK fratricide in the absence of 2B4-CD48 interaction is dependent on perforin both in vitro and in vivo. 2B4 has been reported to have activating, costimulatory, and inhibitory functions on murine NK cells. 2B4-mediated inhibition of NK-cell fratricide explains some of the paradoxes of 2B4 function reported in studies of murine NK cells. We show that in the absence of 2B4 signaling, activated NK cells have defective cytotoxicity and proliferation because of fratricide and not due to the absence of a 2B4-dependent activation signal.
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Somanchi, Srinivas S., Anitha Gururajan, Laurence J. N. Cooper, and Dean A. Lee. "NK-Cell Acquisition of Chemokine Receptors From Engineered Antigen Presenting Cells." Blood 116, no. 21 (November 19, 2010): 1744. http://dx.doi.org/10.1182/blood.v116.21.1744.1744.
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Abstract Abstract 1744 Natural Killer (NK) cells are able to extract fragments of cell membrane from antigen presenting cells through the immunological synapse, functionally incorporating the membrane receptors contained therein by a process called trogocytosis. Recently it was demonstrated that NK cells can acquire functional CCR7 from dendritic cells through this process and migrate in response to chemokines (CCL19 and CCL21). We investigated whether this process could be used to transiently modify NK cells ex vivo without genetic intervention. In previous work, we developed a K562-based artificial antigen presenting cell (aAPC) expressing membrane-bound IL-21 (K562-cl9-mIL21) which enables robust NK-cell expansion, and determined that NK cells did not express detectable CCR7 during this process. To investigate trogocytosis in this system, we genetically modified K562-cl9-mIL21 to express membrane-bound CCR7 (K562 cl9 mIL21CCR7) using the Sleeping Beauty transposon/transposase system. After 24 hours of co-culture the NK cells cultured with K562-cl9-mIL21CCR7 demonstrated marked surface expression of CCR7 compared to NK cells cultured on K562-cl9-mIL21 (Figure 1a). In kinetic experiments using three independent donors, CCR7 peak uptake occured at 24 hours (Figure 1b), followed by a decline that corresponded with the loss of aAPCs in the cultures due to lysis by NK cells. This demonstrates that NK cells can be transiently modified during in vitro expansion to bear receptors that are otherwise not a normal part of their transcriptional repertoire. We are currently establishing the functionality of trogocytosed receptors in vitro and in vivo, and investigating the kinetics of CCR7 persistence after removal of the aAPCs. However, even transient expression as demonstrated might be sufficient for bestowing novel NK-cell migration ability in vivo in response to chemokine signaling, giving the engineered NK cells ability to reach desired tissue targets. Disclosures: Lee: Altor BioScience Corp: Research Funding; Celgene: Research Funding.
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Sarvaria, Anushruti, Robert David Danby, J. Alejandro Madrigal, and Aurore Saudemont. "Cord Blood IL-15 Activated NK Cells Increase Cord Blood CD34+CD133+CD45lo Cell Function through IFN-y Production and Direct Cell Contact." Blood 132, Supplement 1 (November 29, 2018): 2032. http://dx.doi.org/10.1182/blood-2018-99-111820.
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Abstract Delayed engraftment following cord blood (CB) transplantation remains a significant challenge. While cell dose is clearly limiting, CB derived hematopoietic stem cells (HSCs) also exhibit a deficit in homing and engraftment. IL-15 activated natural killer (NK) cells have been shown as potential promoters of homing and engraftment of CB HSCs. However, the role of NK cells and their underlying mechanisms in promoting CB HSCs requires further study. Here, we explore the effect of IL-15 activated CB NK cells on the functional properties of CB CD34+CD133+CD45lo HSCs. In addition, we define the mechanistic interaction between NK cells and HSCs that may increase CB-HSC engraftment and improve patient outcome post-HSC transplantation. We first determined whether IL-15 activated NK cells could improve HSC function in vitro. Purified CD56+CD3- NK cells from CB were stimulated overnight with IL-15 and cultured at a 1:5 cell ratio with autologous purified CD34+CD133+CD45lo cells (CB HSCs). IL-15 activated NK cells increased CXCR4 expression on CB HSCs when compared to cultures with resting NK cells or CB HSCS alone. As HSCs must migrate to the bone marrow in order to engraft and facilitate long-term immune reconstitution, we next assessed whether NK cells also impact on HSC migration, clonogenicity and proliferation. We found that elevated levels of CXCR4 on CB HSCs cultured with activated NK cells also translated into enhanced chemotaxis towards SDF-1α in vitro. IL-15 activated CB NK cells also increased CB HSC clonogenicity as evaluated by short-term in vitro cultures. The effect of activated NK cells on the clonogenic capacity of CB HSCs was cell dose dependent with the highest effect observed at a ratio of 1:10. To study CB HSC proliferation, CFSE stained CD34+CD133+CD45lo cells were cultured either alone, with resting NK cells or IL-15 activated NK cells. Cultures with IL-15 activated NK cells significantly increased CB HSC proliferation when compared to cultures with resting NK cells or CB HSCs alone [median percentage of proliferating CB-HSCs; 38.4% (34%-44.6%) vs. 46.7% (36%-53.4%) vs. 69% (59.6%-78.5%)]. Moreover, following the ability of IL-15 activated NK cells to upregulate CB HSC proliferation, we investigated whether CB HSCs still retained their long-term engraftment potential. We found that proliferating CB HSCs still recalled both their short-term and long term clonogenic capacity as evaluated by CFU assays and cobblestone cultures followed by long-term culture (LTC-IC) respectively. Finally, we demonstrated that IL-15 activated NK cells also possessed the ability to activate pAkt/pErk and pStat3. As pAkt/pErk and pStat3 are key mediators of cell survival proliferation, our findings identify that NK cells may promote the survival and proliferation of CB HSCs through activating pAkt/pErk and pStat3. These data suggest that IL-15 activated NK cells from CB are endowed with properties to promote the functional profile of CB HSCs that contribute to improved engraftment. To further understand the underlying mechanisms through which IL-15 activated NK cells exert their ability to upregulate the functional profile of CB HSCs, we used antibody blockade experiments. We showed that the ability of NK cells to increase CXCR4 expression on CB HSCs was mediated via the provision of IFN-γ, but not TNF-α or TNF-β. Whereas, the effect of NK cells on CB HSC function studied through clonogenicity, proliferation and signalling studies was only partially dependent on IFN-γ production by IL-15 activated NK cells. Using transwell experiments, we further determined that the ability of activated NK cells to upregulate CB HSC function is also partly dependent on direct NK cell/HSC cell contact. Subsequently, we found that the addition of blocking antibody against 2B4 in cultures containing IL-15 activated NK cells and CB HSC partially reversed the ability of NK cells to increase the clonogenic capacity, proliferation and Akt/Erk and Stat3 signalling of CB HSCs. Thus, the ability of IL-15 activated NK cells to increase the functional profile of CB HSCs depends on IFN-γ production and cell-cell contact involving 2B4. Our combined studies demonstrate a novel effect of IL-15 activated CB NK cells and their key factors as potential mediators of stem cell homing and engraftment, which could be utilized to develop strategies that will benefit all patients with haematological malignancies and improve CB transplantation. Disclosures No relevant conflicts of interest to declare.