Artificial Antigen Presenting Cells (aAPC) Expanded NK-Mediated Enhanced Lysis of Allogeneic Tumor Cells Regardless of HLA Class I/KIR Mismatch and Its Implication of Use in Eradicating Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3023-3023
Author(s):  
Hua Zhang ◽  
Bruce Levine ◽  
Nga Voong ◽  
Alan S. Wayne ◽  
Carl H. June ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Fusion Proteins ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Target Cells ◽  
Activating Receptors

Abstract Abstract 3023 Poster Board II-999 NK Killer cell immunoglobulin-like receptors (KIRs) and their human leukocyte antigen (HLA) ligands play critical roles in maintaining natural killer (NK) cell tolerance, while providing surveillance against pathogens and malignant transformation. Natural killer (NK) cells have been explored as tools for adoptive anti-tumor or leukemia immunotherapy and current models hold that a mismatch or absence of KIR ligands on target cells is essential for efficient NK cell mediated cytolysis. However, new approaches are now available to activate NK cells and the role for KIR mediated signaling in regulating cytotoxicity of activated NK cells has not been well studied. In this study, aAPCs comprising IL15Ra+K562 cells engineered to express 4-1BBL activated and expanded peripheral NK cells in the presence of exogenous IL15 up to 1000-fold in 3 weeks. Compared to resting NK cells, 4-1BBL/IL15-activated NK cells upregulated TRAIL and NKp30, 44, 46 expression, and showed significantly enhanced cytotoxicity against a multitude of tumor targets including K562, Daudi, Ewing's tumors, osteosarcoma, as well as autologous tumors (50%-90% killing vs. 0%-8% with non-activated NK cells). Meanwhile we could detect little to no influence of KIR signaling in regulating cytotoxicity by aAPC activated NK cells, since sorted CD158a+ and CD158b+ activated NK cells showed similar killing of tumor cells expressing HLA group C1 (CD158b ligand) and/or C2 (CD158a ligand) antigens. In contrast, killer activating receptors (KARs) were indispensable for the cytolysis of solid pediatric tumors by aAPC-activated NK cells, since the killing was significantly inhibited by fusion proteins binding to the ligands of NKG2D, NK p30, p44, p46, p80 (KARs). About 20-40% inhibition of the killing was accomplished when all four activating receptors were blocked, though other activating receptors have not been well defined. Although acute lymphoblastic leukemia (ALL) blasts were refractory to fresh NK cytotoxicity, 4-1BBL/IL15 activated NK cells demonstrated higher lytic activities (20%-50%) against ALL blasts from either patients or cell lines. ALL blast lysis could be completely or partially inhibited by KAR-blocking fusion proteins, indicating that expression levels of KAR ligands vary among ALL cases and other solid tumors. We conclude that KIR ligand mismatch or absence is not essential for effective NK cytotoxicities on either solid tumors or ALL when fully activated NK cells are utilized. This suggests that adoptive therapy with autologous aAPC-activated NK cells may prove effective in some clinical settings, such as ALL, AML, or certain solid tumors. Further studies to assess the impact of KAR ligand expression on aAPC-activated NK killing of ALL blasts are in progress. Percentage of Activated NK Killings vs. Fresh NK's with/without KAR-Ig Fusion Proteins Activated NK (E:T=2.5:1) Fresh NK (E:T=25:1) -KAR-Ig Fc +KAR-Ig Fc SB tumor (Ewing's) 48% 30% 0.5% HOS (Osteo sarcoma) 63% 36% 0.7% Daudi (B. lymphoma) 78% 46% 0.2% REH (ALL) 54% 8% 3% Disclosures No relevant conflicts of interest to declare.

scholarly journals 799 Neoantigen-cytokine-chemokine multifunctional natural killer cell engager for immunotherapy of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A834-A834
Author(s):  
Xue Yao ◽  
Sandro Matosevic
Keyword(s):  
Tumor Microenvironment ◽  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Nk Cell Therapy

BackgroundThe effectiveness of natural killer (NK) cell-based immunotherapy against solid tumors is limited by the lack of specific antigens and the immunosuppressive tumor microenvironment (TME). Glioblastoma multiforme (GBM) is one such heavily immunosuppressive tumor that has been particularly hard to target and remains without a viable treatment. The development of novel approaches to enhance the efficacy of NK cells against GBM is urgently needed. NK cell engagers (NKCE) have been developed to enhance the efficacy of NK cell therapy.MethodsTo improve the clinical efficacy of NK cell therapy, we are developing a new generation of multi-specific killer engagers, which consists of a neoantigen-targeting moiety, together with cytokine and chemokine-producing domains. Neoantigens are new antigens formed specifically in tumor cells due to genome mutations, making them highly specific tools to target tumor cells. Our engager has been designed to target Wilms' tumor-1 (WT-1), a highly specific antigen overexpressed in GBM among other solid tumors. This is done through the generation of an scFv specific targeting the complex of WT-1126-134/HLA-A*02:01 on the surface of GBM. On the NK cell side, the engager is designed to target the activating receptor NKp46. Incorporation of the cytokine IL-15 within the engager supports the maturation, persistence, and expansion of NK cells in vivo while favoring their proliferation and survival in the tumor microenvironment. Additionally, our data indicated that the chemokine CXCL10 plays an important role in the infiltration of NK cells into GBM, however, GBM tumors produce low levels of this chemokine. Incorporation of a CXCL10-producing function into our engager supports intratumoral NK cell trafficking by promoting, through their synthetic production, increased levels of CXCL10 locally in the tumor microenvironment.ResultsCollectively, this has resulted in a novel multifunctional NK cell engager, combining neoantigen-cytokine-chemokine elements fused to an activating domain-specific to NK cells, and we have investigated its ability to support and enhance NK cell-mediated cytotoxicity against solid tumors in vitro and in vivo against patient-derived GBM models. The multi-specific engager shows both high tumor specificity, as well as the ability to overcome NK cell dysfunction encountered in the GBM TME.ConclusionsWe hypothesize that taking advantage of our multi-functional engager, NK cells will exhibit superior ex vivo expansion, infiltration, and antitumor activity in the treatment of GBM and other solid tumors.

Natural Killer Cells In Pediatric Acute Lymphoblastic Leukemia Patients At Diagnosis Demonstrate An Inhibitory Phenotype and Reduced Cytolytic Capacity

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1397-1397 ◽  
Author(s):  
Rayne H. Rouce ◽  
Takuya Sekine ◽  
Gerrit Weber ◽  
Claude Chew ◽  
Katayoun Rezvani ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Nk Cells ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Target Cells ◽  
Healthy Controls ◽  
Cytokine Release ◽  
Absolute Count ◽  
Flow Cytometric ◽  
Pediatric All

Abstract Background Natural killer (NK) cells are a key component of innate immunity, with the potential to recognize and kill transformed malignant cells without prior sensitization. A balance between activating and inhibitory signals from cell surface receptors determines NK cell cytotoxicity and cytokine release. Therapeutic approaches to augmenting NK cell function are being explored in various malignancies. Little is known about NK phenotype and function in patients with childhood acute lymphoblastic leukemia (ALL), the most common childhood cancer. Here we describe an inhibitory phenotype and impaired cytolytic function in NK cells from pediatric ALL patients at diagnosis, compared with healthy pediatric controls. Restoring NK function may be a useful therapeutic approach in ALL. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 25 patients with newly diagnosed B-ALL, age 1-16 years, and 7 healthy controls, age 2-13 years, in order to compare NK cell frequency, immunophenotype, and functional activity. NK frequency was assessed by flow cytometric staining for CD56+CD3- cells. NK phenotype was assessed by surface expression of activating receptors NKp30, NKp44, NKp46 and NKG2D and inhibitory receptors KIR2DL1/S1, KIR2DL2/S2, KIR3DL1 and NKG2A. Functional activity was determined by incubation of NKs with target cells, followed by flow cytometric measurement of degranulation (surface CD107a) and cytokine release (intracellular IFNg and TNFa). Targets included the MHC class I deficient K562 cell line and, where available, autologous ALL blasts. Results ALL patients demonstrated significantly lower absolute NK cell counts compared with healthy controls (mean absolute count 168 vs. 406 cells/uL, p = 0.0002). They also exhibited significantly fewer NK cells expressing the activating marker NKp46 (mean absolute count 70 vs. 165, p = 0.016); and a significantly higher percentage of cells expressing the inhibitory marker NKG2A (mean 20.5% vs. 1.95% in controls, p = 0.012) (Fig 1A). In co-culture assays with K562 target cells, ALL patients' NK cells demonstrated inferior degranulation and cytokine release compared to healthy controls (representative data in Fig 1B; mean IFNγ production of 1.2% vs. 4.8%, p = 0.02; mean TNFα production of 1.8% vs. 3.8%, p = 0.06; and mean surface CD107a of 5.4% vs. 15.1%, p = 0.08). ALL samples (n = 3) demonstrated little to no cytokine release when incubated with autologous blasts compared with the response elicited by PMA-ionomycin (representative data in Fig 1C; mean CD107a 0.92% vs. 7.85%, p = 0.04; mean IFNγ 0.26% vs 40.47%, p = 0.10; mean TNFα 0.2% vs 41%, p = 0.008). Conclusion At diagnosis, pediatric ALL patients exhibit a lower frequency of NK cells, an inhibitory phenotype, and decreased cytolytic activity compared to healthy pediatric controls, particularly against autologous leukemic blasts. These results suggest that augmentation of the NK response may be useful therapeutically to improve outcomes in childhood ALL. Disclosures: No relevant conflicts of interest to declare.

Fusion Proteins of Ligands for NKG2D and CD20-Directed ScFvs Sensitize Lymphomas for NK Cell-Mediated Lysis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2843-2843
Author(s):  
Christian Kellner ◽  
Daniela Hallack ◽  
Pia Glorius ◽  
Matthias Staudinger ◽  
Sahar Mohseni Nodehi ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Fusion Proteins ◽  
Nk Cell ◽  
Effector Cells ◽  
Healthy Donors

Abstract Abstract 2843 Natural killer group 2 member D (NKG2D) is an important activating receptor controlling cytotoxicity of natural killer (NK) cells and T cells and plays an important role in immune surveillance against tumors. For redirecting NK cells to B-lymphoid tumor cells two recombinant bifunctional antibody-based fusion proteins were designed in order to coat malignant cells with ligands for NKG2D and attract NK cells. Therefore, a human CD20-directed single-chain fragment variable (scFv) was fused to NKG2D-specific ligands, either MHC class I chain-related protein A (MICA) or unique long 16-binding protein 2 (ULBP2). These two fully human fusion proteins, designated MICA:CD20 and ULBP2:CD20, respectively, were expressed in eukaryotic cells and purified to homogeneity. Size exclusion chromatography revealed that both purified proteins predominantly formed monomers. MICA:CD20 and ULBP2:CD20 specifically and simultaneously bound to CD20 and NKG2D and efficiently mediated lysis of lymphoma cell lines with mononuclear cells from healthy donors as effector cells. Analysis of the activation status of NKG2D-positive T cells and NK cells revealed that MICA:CD20 and ULBP2:CD20 activated resting NK cells, but not T cells, indicating that NK cells were the relevant effector cell population for the two molecules. In cytotoxicity assays using human NK cells from healthy donors, both agents sensitized lymphoma cell lines as well as fresh tumor cells for NK cell-mediated lysis. MICA:CD20 and ULBP2:CD20 induced lysis at low nanomolar concentrations with half maximum effective concentrations between 1 and 4 nM depending on target cells. Interestingly, ULBP2:CD20 exhibited a higher cytolytic potential than MICA:CD20 in terms of maximum lysis. Importantly, MICA:CD20 and ULBP2:CD20 induced lysis of 13/13 tested primary tumor cell samples from patients with different B cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma and marginal zone lymphoma. Interestingly, cell surface expression of endogenous MICA and ULBP2 was low or not detectable on fresh tumor cells. In addition, ULBP2:CD20 was also capable of inducing lysis of tumor cells in cytotoxicity experiments using autologous patient-derived NK cells as effector cells, indicating that the triggering signal was sufficient to overcome inhibition by interactions between killer cell immunoglobulin-like receptors and MHC class I molecules. Moreover, both MICA:CD20 and ULBP2:CD20 synergistically enhanced antibody-dependent cellular cytotoxicity (ADCC) by the monoclonal antibody daratumumab directed against CD38 which is co-expressed together with CD20 on certain B cell lymphomas. This approach of simultaneously triggering ADCC and natural cytotoxicity by these bifunctional fusion proteins may represent a promising strategy to achieve stronger NK cell-mediated antitumor responses. Disclosures: de Weers: Genmab : Employment. van De Winkel:Genmab: Employment. Parren:Genmab: Employment.

scholarly journals CD38 contributes to human natural killer cell responses through a role in immune synapse formation

2018 ◽  
Author(s):  
Mathieu Le Gars ◽  
Christof Seiler ◽  
Alexander W. Kay ◽  
Nicholas L. Bayless ◽  
Elsa Sola ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synapse Formation ◽  
Cell Function ◽  
Nk Cell ◽  
Critical Role ◽  
Target Cells ◽  
Immune Synapse ◽  
Ifn Γ

AbstractNatural killer (NK) cells use a diverse array of activating and inhibitory surface receptors to detect threats and provide an early line of defense against viral infections and cancer. Here, we demonstrate that the cell surface protein CD38 is a key human NK cell functional receptor through a role in immune synapse formation. CD38 expression marks a mature subset of human NK cells with a high functional capacity. NK cells expressing high levels of CD38 display enhanced killing and IFN-γ secretion in response to influenza virus-infected and tumor cells. Inhibition of CD38 enzymatic activity does not influence NK cell function, but blockade of CD38 and its ligand CD31 abrogates killing and IFN-γ expression in response to influenza-infected cells. Blockade of CD38 on NK cells similarly inhibits killing of tumor cells. CD38 localizes and accumulates at the immune synapse between NK cells and their targets, and blocking CD38 severely abrogates the ability of NK cells to form conjugates and immune synapses with target cells. Thus, CD38 plays a critical role in NK cell immune synapse formation. These findings open new avenues in immunotherapeutic development for cancer and infection by revealing a critical role for CD38 in NK cell function.

Enhanced Elimination of 6-Mercaptopurine or Methotrexate-Treated Acute Lymphoblastic Leukemia Cells by Natural Killer Lymphocytes In Vitro: A Potential Mechanism of Action of Maintenance Chemotherapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2128-2128 ◽  
Author(s):  
Abdual H. Siddiqui ◽  
Mohammad Bhuiyan ◽  
Akila Muthukumar ◽  
Steven Buck ◽  
Yaddanapudi Ravindranath ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Drug Exposure ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Target Cells ◽  
Lymphoma Cells ◽  
Nkg2d Ligands ◽  
Reh Cells

Abstract Abstract 2128 Background: Maintenance chemotherapy (MC) is an important component of childhood B-precursor acute lymphoblastic leukemia (ALL) therapy; however, it is not necessary in the treatment of mature B cell neoplasms. The operational mechanisms of MC are not understood. Improvement in immunologic function including near normal levels of natural killer (NK) lymphocytes was reported during ALL MC. We hypothesize that in addition to their direct cytotoxicity, MC drugs alter surviving lymphoblasts, rendering them susceptible to innate immune response, likely through cell mediated cytotoxicity via stress proteins such as NKG2D ligands, co-stimulatory or adhesion molecules. Objective: The effect of 6-mercaptopurine (6MP) or methotrexate (MTX) treatment of B-precursor and mature B leukemia/lymphoma cells in their elimination by NK lymphocytes was investigated in this study. Design and Methods: Allogeneic NK cell-mediated elimination of REH (TEL/AML-positive B-precursor ALL) and Raji (mature B cell lymphoma) cells treated with standard MC drugs was studied. High dose cytarabine (Ara-C) and MTX are used during the consolidation chemotherapy; therefore, Ara-C and MTX-resistant REH and Raji cell sub-lines were established by exposing wild type cells to increasing concentrations of drugs over several months. Natural killer cells from 17 healthy volunteers were separated using the MACS NK cell isolation kit. After purity evaluation, NK cells were incubated with interleukin-15 overnight. Leukemia cells were incubated in minimally toxic (20% cytotoxicity) concentrations of 6MP and MTX. The leukemia/lymphoma cells were then co-incubated with NK cells at different ratios. The NK cell-mediated leukemia/lymphoma cell cytotoxicity was measured by flow cytometric cell-mediated cytotoxicity assay, marking effector cells with lineage-specific monoclonal antibodies and staining target cells with propidium iodide and annexin-V and using microspheres for quantification of viable and apoptotic cells. The level of resistance of the respective cell sub-lines was evaluated using MTT assay. We also investigated whether NK cell exposure to same concentrations of MC drugs before co-incubation alters cytotoxicity. Surface expression of NKG2D ligands, ULBP 1, 2 and 3, MICA and MICB was studied by flow cytometry. Results: 6-mercaptopurine treatment of REH cells and MTX treatment of Raji cells resulted in enhanced NK cell-mediated elimination when compared to untreated cells by 25% and 20%, respectively. The results were similar when NK cells were exposed to the same concentrations of MC drugs before co-incubation, indicating lack of negative effect of the drug exposure in NK cells’ ability to kill. Similar experiments were conducted on resistant cells, in order to make the target cells more comparable to the residual lymphoblasts during MC. Most interestingly, the REH cells, but not the Raji cells, resistant to Ara-C and MTX showed about 14% and 4% enhancement of NK cell-mediated killing, respectively, after being exposed to the minimally toxic concentrations of MC drugs. This indicates that resistant B precursor ALL cells can be eliminated by NK cells upon MC drug exposure, but not mature B lymphoblasts, in this experimental setting. No increase in the expression of NKG2D ligands on drug treated ALL cells was observed. Conclusion: These findings suggest that enhanced susceptibility of drug-exposed leukemia cells to innate immune response may be an operational mechanism of MC. This mechanism may involve pathways other than NKG2D. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chemiluminescence response of human natural killer cells. I. The relationship between target cell binding, chemiluminescence, and cytolysis.

1982 ◽  
Vol 156 (2) ◽  
pp. 492-505 ◽  
Author(s):  
S L Helfand ◽  
J Werkmeister ◽  
J C Roder
Keyword(s):  
Tumor Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Cell Lines ◽  
Target Cell ◽  
Nk Cell ◽  
Target Antigen ◽  
Target Cells ◽  
Tumor Cell Lines

The binding of tumor cells or fetal fibroblasts to human natural killer (NK) cells led to a rapid chemiluminescence response within seconds of target-effector interaction. The degree of chemiluminescence was dependent on the concentration of NK-enriched lymphocytes or target cells, and plasma membrane vesicles from K562 also induced a chemiluminescence response. Mild glutaraldehyde treatment of effector cells abrogated their ability to generate chemiluminescence, whereas K562 target cells treated in the same way were almost fully able to induce a chemiluminescence response to NK-enriched lymphocytes. These results show a directionality of response with NK as the responders and tumor cells as the stimulators. A survey of eight different tumor cell lines and fetal fibroblast lines revealed a striking correlation (r greater than 0.93, P less than 0.001) between the ability of a given line to bind to NK-enriched lymphocytes, induce chemiluminescence, and to be lysed. Three differentiated sublines of K562 grown in butyrate and cloned induced little chemiluminescence compared with the K562 parent, and they were selectively resistant to NK-mediated binding and cytolysis. In addition, treatment of K562 cells with higher concentrations of glutaraldehyde for longer periods led to varying degrees of target antigen preservation, as measured in cold target competition assays and in conjugate formation. The degree of NK target antigen preservation correlated directly with the ability of the cells to induce chemiluminescence (r greater than 0.95). The degree of NK activation was also important because interferon-pretreated effectors generated more chemiluminescence upon stimulation with K562 or MeWo targets. Monocytes or granulocytes did not contribute to the chemiluminescence induced by NK-sensitive targets. Some NK-resistant tumor cell lines were sensitive to monocyte-mediated cytolysis and also induced chemiluminescence in monocytes but not NK cells. These results show that the target structures recognized by the NK cell may play a role in NK activation because the degree of chemiluminescence was directly proportional to the ability of a given target cell line to bind to the NK cell and to be lysed.

Mechanisms of Natural Killer Cell Evasion Through Viral Adaptation

2020 ◽  
Vol 38 (1) ◽  
pp. 511-539
Author(s):  
Mathieu Mancini ◽  
Silvia M. Vidal
Keyword(s):  
Immune System ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Target Cells ◽  
Activating Receptors ◽  
Viral Adaptation ◽  
Antiviral Function

The continuous interactions between host and pathogens during their coevolution have shaped both the immune system and the countermeasures used by pathogens. Natural killer (NK) cells are innate lymphocytes that are considered central players in the antiviral response. Not only do they express a variety of inhibitory and activating receptors to discriminate and eliminate target cells but they can also produce immunoregulatory cytokines to alert the immune system. Reciprocally, several unrelated viruses including cytomegalovirus, human immunodeficiency virus, influenza virus, and dengue virus have evolved a multitude of mechanisms to evade NK cell function, such as the targeting of pathways for NK cell receptors and their ligands, apoptosis, and cytokine-mediated signaling. The studies discussed in this article provide further insights into the antiviral function of NK cells and the pathways involved, their constituent proteins, and ways in which they could be manipulated for host benefit.

scholarly journals Strategies to Augment Natural Killer (NK) Cell Activity against Solid Tumors

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1040 ◽  
Author(s):  
Ziqing Chen ◽  
Ying Yang ◽  
Lisa L. Liu ◽  
Andreas Lundqvist
Keyword(s):  
Immune System ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Antigen Processing ◽  
Nk Cell ◽  
Clinical Responses

The immune system plays a crucial role to prevent local growth and dissemination of cancer. Therapies based on activating the immune system can result in beneficial responses in patients with metastatic disease. Treatment with antibodies targeting the immunological checkpoint axis PD-1 / PD-L1 can result in the induction of anti-tumor T cell activation leading to meaningful long-lasting clinical responses. Still, many patients acquire resistance or develop dose-limiting toxicities to these therapies. Analysis of tumors from patients who progress on anti-PD-1 treatment reveal defective interferon-signaling and antigen presentation, resulting in immune escape from T cell-mediated attack. Natural killer (NK) cells are innate lymphocytes that can kill tumor cells without prior sensitization to antigens and can be activated to kill tumor cells that have an impaired antigen processing and presentation machinery. Thus, NK cells may serve as useful effectors against tumor cells that have become resistant to classical immune checkpoint therapy. Various approaches to activate NK cells are being increasingly explored in clinical trials against cancer. While clinical benefit has been demonstrated in patients with acute myeloid leukemia receiving haploidentical NK cells, responses in patients with solid tumors are so far less encouraging. Several hurdles need to be overcome to provide meaningful clinical responses in patients with solid tumors. Here we review the recent developments to augment NK cell responses against solid tumors with regards to cytokine therapy, adoptive infusion of NK cells, NK cell engagers, and NK cell immune checkpoints.

scholarly journals Recruitment and Activation of Natural Killer (Nk) Cells in Vivo Determined by the Target Cell Phenotype

2000 ◽  
Vol 191 (1) ◽  
pp. 129-138 ◽  
Author(s):  
Rickard Glas ◽  
Lars Franksson ◽  
Clas Une ◽  
Maija-Leena Eloranta ◽  
Claes Öhlén ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Interferon Γ ◽  
Class I ◽  
Cell Phenotype ◽  
Target Cells

Natural killer (NK) cells can spontaneously lyse certain virally infected and transformed cells. However, early in immune responses NK cells are further activated and recruited to tissue sites where they perform effector functions. This process is dependent on cytokines, but it is unclear if it is regulated by NK cell recognition of susceptible target cells. We show here that infiltration of activated NK cells into the peritoneal cavity in response to tumor cells is controlled by the tumor major histocompatibility complex (MHC) class I phenotype. Tumor cells lacking appropriate MHC class I expression induced NK cell infiltration, cytotoxic activation, and induction of transcription of interferon γ in NK cells. The induction of these responses was inhibited by restoration of tumor cell MHC class I expression. The NK cells responding to MHC class I–deficient tumor cells were ∼10 times as active as endogenous NK cells on a per cell basis. Although these effector cells showed a typical NK specificity in that they preferentially killed MHC class I–deficient cells, this specificity was even more distinct during induction of the intraperitoneal response. Observations are discussed in relation to a possible adaptive component of the NK response, i.e., recruitment/activation in response to challenges that only NK cells are able to neutralize.

scholarly journals Exploitation of natural killer cells for the treatment of acute leukemia

Blood ◽  
2016 ◽  
Vol 127 (26) ◽  
pp. 3341-3349 ◽  
Author(s):  
Rupert Handgretinger ◽  
Peter Lang ◽  
Maya C. André
Keyword(s):  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Adoptive Transfer ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Target Cells

Abstract Natural killer (NK) cells play an important role in surveillance and elimination of malignant cells. Their spontaneous cytotoxicity was first demonstrated in vitro against leukemia cell lines, and NK cells might play a crucial role in the therapy of leukemia. NK cell activity is controlled by an array of germ line–encoded activating and inhibitory receptors, as well as modulating coreceptors. This biologic feature can be exploited in allogeneic cell therapy, and the recognition of “missing-self” on target cells is crucial for promoting NK cell–mediated graft-versus-leukemia effects. In this regard, NK cells that express an inhibitory killer immunoglobulin-like receptor (iKIR) for which the respective major histocompatibility complex class I ligand is absent on leukemic target cells can exert alloreactivity in vitro and in vivo. Several models regarding potential donor–patient constellations have been described that have demonstrated the clinical benefit of such alloreactivity of the donor-derived NK cell system in patients with adult acute myeloid leukemia and pediatric B-cell precursor acute lymphoblastic leukemia after allogeneic stem cell transplantation. Moreover, adoptive transfer of mature allogeneic NK cells in the nontransplant or transplant setting has been shown to be safe and feasible, whereas its effectivity needs further evaluation. NK cell therapy can be further improved by optimal donor selection based on phenotypic and genotypic properties, by adoptive transfer of NK cells with ex vivo or in vivo cytokine stimulation, by the use of antibodies to induce antibody-dependent cellular cytotoxicity or to block iKIRs, or by transduction of chimeric antigen receptors.

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