scholarly journals Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2500
Author(s):  
Cristina Capuano ◽  
Chiara Pighi ◽  
Simone Battella ◽  
Davide De Federicis ◽  
Ricciarda Galandrini ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Targeting ◽  
Nk Cell ◽  
Intrinsic Resistance ◽  
Cell Functions ◽  
Adaptive Immune ◽  
Cytokines And Chemokines ◽  
Affinity Receptor ◽  
Immunosuppressive Microenvironment

Natural killer (NK) cells hold a pivotal role in tumor-targeting monoclonal antibody (mAb)-based activity due to the expression of CD16, the low-affinity receptor for IgG. Indeed, beyond exerting cytotoxic function, activated NK cells also produce an array of cytokines and chemokines, through which they interface with and potentiate adaptive immune responses. Thus, CD16-activated NK cells can concur to mAb-dependent “vaccinal effect”, i.e., the development of antigen-specific responses, which may be highly relevant in maintaining long-term protection of treated patients. On this basis, the review will focus on strategies aimed at potentiating NK cell-mediated antitumor functions in tumor-targeting mAb-based regimens, represented by (a) mAb manipulation strategies, aimed at augmenting recruitment and efficacy of NK cells, such as Fc-engineering, and the design of bi- or trispecific NK cell engagers and (b) the possible exploitation of memory NK cells, whose distinctive characteristics (enhanced responsiveness to CD16 engagement, longevity, and intrinsic resistance to the immunosuppressive microenvironment) may maximize therapeutic mAb antitumor efficacy.

Reciprocal Interaction of Monocytes and NK Cells by Activation-Induced Expression of Ligands for the Activating Immunoreceptor NKG2D.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2212-2212
Author(s):  
Matthias Krusch ◽  
Mercedes Kloss ◽  
Andrea Peterfi ◽  
Ingrid Kumbier ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Adaptive Immune System ◽  
Surface Expression ◽  
Pcr Analysis ◽  
High Plasticity ◽  
Blood Monocytes ◽  
Cell Functions ◽  
Adaptive Immune ◽  
Mrna Induction

Abstract Reciprocal Interactions of NK cells with Dendritic Cells (DC) can induce activation of NK cells, maturation or lysis of DC and influence subsequent adaptive immune responses. However, little is known about the interaction of peripheral blood monocytes with NK cells, especially regarding involved immunoregulatory surface molecules. Here we report that monocytes express ligands for the activating immunoreceptor NKG2D expressed on NK cells upon treatment with various stimuli. Incubation of monocytes with TNF, GM-CSF, IFN-g and various TLR ligands (LPS, Pam3Cys, R848, PolyI:C) induced surface expression of the NKG2D ligands (NKG2DL) MICA and to a lesser extent MICB, but no relevant changes of ULBP molecules, as determined by FACS analysis. Expression was confirmed by quantitative PCR analysis of NKG2DL mRNA induction. To elucidate the functional consequences of NKG2DL expression on monocytes for NK cell functions we performed coculture assays of monocytes and autologous NK cells. NKG2DL expression on stimulated monocytes lead to a significant induction of IFN-g release into the culture supernatant by NK cells as determined by ELISA. This IFN-g release was blocked by addition of a NKG2D-Ig fusionprotein, but not by isotype control demonstrating that the induction of NK cell IFN-g production was in fact specifically due to NKG2DL expression on monocytes. Since both monocytes and NK cells rapidly migrate to sites of inflammation, and monocytes display a high plasticity regarding their function and maturation which is influenced by IFN-g, our data indicate that NKG2DL expression on monocytes might not only mediate reciprocal activation of NK cells and monocytes but also might influence other components of the innate and adaptive immune system and thereby determine the course of subsequent immune reactions.

scholarly journals Wilms’ Tumor Primary Cells Display Potent Immunoregulatory Properties on NK Cells and Macrophages

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 224
Author(s):  
Piera Filomena Fiore ◽  
Paola Vacca ◽  
Nicola Tumino ◽  
Francesca Besi ◽  
Andrea Pelosi ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Wilms Tumor ◽  
Primary Cultures ◽  
Primary Cells ◽  
Alternatively Activated Macrophages ◽  
Cell Functions ◽  
Inhibitory Mechanisms ◽  
Defensive Role ◽  
Immunosuppressive Microenvironment

The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm’s Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56+/CD133−) or an epithelial (CD56−/CD133+) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression.

scholarly journals GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1802
Author(s):  
Nayoung Kim ◽  
Mi Yeon Kim ◽  
Woo Seon Choi ◽  
Eunbi Yi ◽  
Hyo Jung Lee ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Negative Regulator ◽  
Target Cells ◽  
Dependent Manner ◽  
Cell Functions ◽  
Cell Based Therapy ◽  
Activating Receptors ◽  
Gsk 3Β

Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.

scholarly journals Role and Modulation of NK Cells in Multiple Myeloma

Hemato ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 167-181
Author(s):  
Marie Thérèse Rubio ◽  
Adèle Dhuyser ◽  
Stéphanie Nguyen
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Proteasome Inhibitors ◽  
Disease Evolution ◽  
Cell Functions

Myeloma tumor cells are particularly dependent on their microenvironment and sensitive to cellular antitumor immune response, including natural killer (NK) cells. These later are essential innate lymphocytes implicated in the control of viral infections and cancers. Their cytotoxic activity is regulated by a balance between activating and inhibitory signals resulting from the complex interaction of surface receptors and their respective ligands. Myeloma disease evolution is associated with a progressive alteration of NK cell number, phenotype and cytotoxic functions. We review here the different therapeutic approaches that could restore or enhance NK cell functions in multiple myeloma. First, conventional treatments (immunomodulatory drugs-IMids and proteasome inhibitors) can enhance NK killing of tumor cells by modulating the expression of NK receptors and their corresponding ligands on NK and myeloma cells, respectively. Because of their ability to kill by antibody-dependent cell cytotoxicity, NK cells are important effectors involved in the efficacy of anti-myeloma monoclonal antibodies targeting the tumor antigens CD38, CS1 or BCMA. These complementary mechanisms support the more recent therapeutic combination of IMids or proteasome inhibitors to monoclonal antibodies. We finally discuss the ongoing development of new NK cell-based immunotherapies, such as ex vivo expanded killer cell immunoglobulin-like receptors (KIR)-mismatched NK cells, chimeric antigen receptors (CAR)-NK cells, check point and KIR inhibitors.

NK-dependent DC maturation is mediated by TNFα and IFNγ released upon engagement of the NKp30 triggering receptor

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 566-571 ◽  
Author(s):  
Massimo Vitale ◽  
Mariella Della Chiesa ◽  
Simona Carlomagno ◽  
Daniela Pende ◽  
Maurizio Aricò ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nk Cell ◽  
Interferon Γ ◽  
Cell Functions ◽  
Relevant Role ◽  
Factor Α ◽  
Necrosis Factor ◽  
Dc Maturation

Abstract Natural killer (NK) cells were recently shown to play a relevant role in the process of dendritic cell (DC) maturation. This function is exerted either by direct DC stimulation or through killing those DCs that did not properly acquire a mature phenotype. While killing of immature DCs is dependent on the function of the NKp30 triggering receptor, the mechanism by which NK cells induce DC maturation is still unclear. In this study, we show that also the NK-mediated induction of DC maturation is dependent on NKp30. Upon NK/DC interaction, resulting in NKp30 engagement, NK cells produced tumor necrosis factor α (TNFα) (and interferon γ [IFNγ]) that, in turn, promoted DC maturation. Masking of NKp30 with specific monoclonal antibodies (mAbs) strongly reduced maturation of DCs cocultured with NK cells. In addition, supernatant from NK cells stimulated via NKp30 induced DC maturation, and this effect was neutralized by anti-TNFα antibodies (Abs). This NKp30 function is controlled by the HLA-specific inhibitory NK receptors. Accordingly, the ability to promote maturation was essentially confined to NK cells expressing the killer immunoglobulin-like receptor–negative (KIR–) NKG2Adull phenotype. Finally, the analysis of perforin-deficient NK cells allowed the dissection of the 2 NKp30-mediated NK-cell functions, since NKp30 could induce cytokine-dependent DC maturation in the absence of NK-mediated DC killing.

scholarly journals Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5

2018 ◽  
Vol 116 (3) ◽  
pp. 988-996 ◽  
Author(s):  
Han Wang ◽  
Jianxun Qi ◽  
Shuijun Zhang ◽  
Yan Li ◽  
Shuguang Tan ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Complex Structure ◽  
Binding Mode ◽  
Adaptive Immune ◽  
Binding Interface ◽  
Nk Cell Receptors ◽  
D2 Domain ◽  
Hybrid Complex

Natural killer (NK) cells are important component of innate immunity and also contribute to activating and reshaping the adaptive immune responses. The functions of NK cells are modulated by multiple inhibitory and stimulatory receptors. Among these receptors, the activating receptor CD226 (DNAM-1) mediates NK cell activation via binding to its nectin-like (Necl) family ligand, CD155 (Necl-5). Here, we present a unique side-by-side arrangement pattern of two tandem immunoglobulin V-set (IgV) domains deriving from the ectodomains of both human CD226 (hCD226-ecto) and mouse CD226 (mCD226-ecto), which is substantially different from the conventional head-to-tail arrangement of other multiple Ig-like domain molecules. The hybrid complex structure of mCD226-ecto binding to the first domain of human CD155 (hCD155-D1) reveals a conserved binding interface with the first domain of CD226 (D1), whereas the second domain of CD226 (D2) both provides structural supports for the unique architecture of CD226 and forms direct interactions with CD155. In the absence of the D2 domain, CD226-D1 exhibited substantially reduced binding efficacy to CD155. Collectively, these findings would broaden our knowledge of the interaction between NK cell receptors and the nectin/Necl family ligands, as well as provide molecular basis for the development of CD226-targeted antitumor immunotherapeutics.

scholarly journals The Potential for Cancer Immunotherapy in Targeting Surgery-Induced Natural Killer Cell Dysfunction

Cancers ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 2 ◽  
Author(s):  
Marisa Market ◽  
Katherine Baxter ◽  
Leonard Angka ◽  
Michael Kennedy ◽  
Rebecca Auer
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Clonal Selection ◽  
Killer Cell ◽  
Cancer Recurrence ◽  
Effector Functions ◽  
Cell Dysfunction ◽  
Cell Functions

Natural Killer (NK) cells are granular lymphocytes of the innate immune system that are able to recognize and kill tumor cells without undergoing clonal selection. Discovered over 40 years ago, they have since been recognized to possess both cytotoxic and cytokine-producing effector functions. Following trauma, NK cells are suppressed and their effector functions are impaired. This is especially important for cancer patients undergoing the removal of solid tumors, as surgery has shown to contribute to the development of metastasis and cancer recurrence postoperatively. We have recently shown that NK cells are critical mediators in the formation of metastasis after surgery. While research into the mechanism(s) responsible for NK cell dysfunction is ongoing, knowledge of these mechanisms will pave the way for perioperative therapeutics with the potential to improve cancer outcomes by reversing NK cell dysfunction. This review will discuss mechanisms of suppression in the postoperative environment, including hypercoagulability, suppressive soluble factors, the expansion of suppressive cell populations, and how this affects NK cell biology, including modulation of cell surface receptors, the potential for anergy, and immunosuppressive NK cell functions. This review will also outline potential immunotherapies to reverse postoperative NK dysfunction, with the goal of preventing surgery-induced metastasis.

scholarly journals NK Cell Regulation in Cervical Cancer and Strategies for Immunotherapy

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3104
Author(s):  
Adriana Gutiérrez-Hoya ◽  
Isabel Soto-Cruz
Keyword(s):  
Cervical Cancer ◽  
Nk Cells ◽  
Nk Cell ◽  
Hpv Infection ◽  
Cytolytic Activity ◽  
Cellular Immunotherapy ◽  
Antigen Receptors ◽  
Cytokines And Chemokines ◽  
Hpv Status ◽  
Infected Cells

Cervical cancer is one of the most prevalent gynaecological malignancies worldwide and is related to human papillomavirus (HPV) infection, viral persistence, progression, and invasion. Therefore, the immune response is linked to HPV status. Natural killer (NK) cells play a central role against virus-infected cells and tumours through a delicate balance between activating and inhibitory receptors and secretion of cytokines and chemokines. These cells also play a crucial role in tumour immunosurveillance. For these reasons, there is growing interest in harnessing NK cells as an immunotherapy for cervical cancer. These studies are diverse and include many strategies such as transferring activated autologous or allogeneic NK cells, improving the activation and cytolytic activity of NK cells using cytokines or analogues and modifying chimeric antigen receptors to increase specificity and targeting NK cells. However, research regarding the application of NK cells in immunotherapy is limited. This article focuses on recent discoveries about using NK cells to prevent and treat cervical cancer and the possibility of cellular immunotherapy becoming one of the best strategies to exploit the immune system to fight tumours.

scholarly journals NK Cell-Based Immunotherapy and Therapeutic Perspective in Gliomas

2021 ◽  
Vol 11 ◽  
Author(s):  
Changqing Pan ◽  
You Zhai ◽  
Guanzhang Li ◽  
Tao Jiang ◽  
Wei Zhang
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Primary Brain Tumor ◽  
Therapeutic Approaches ◽  
Independent Manner ◽  
Clinical Prognosis ◽  
Cell Based Therapy ◽  
Current Therapies ◽  
Immunosuppressive Microenvironment ◽  
Therapeutic Perspective

Glioma is the most common malignant primary brain tumor diagnosed in adults. Current therapies are unable to improve its clinical prognosis, imposing the need for innovative therapeutic approaches. The main reason for the poor prognosis is the great cell heterogeneity of the tumor and its immunosuppressive microenvironment. Development of new therapies that avoid this immune evasion could improve the response to the current treatments. Natural killer (NK) cells are an intriguing candidate for the next wave of therapies because of several unique features that they possess. For example, NK cell-based immunotherapy causes minimal graft-versus-host disease. Cytokine release syndrome is less likely to occur during chimeric antigen receptor (CAR)-NK therapy, and CAR-NK cells can kill targets in a CAR-independent manner. However, NK cell-based therapy in treating glioma faces several difficulties. For example, CAR molecules are not sufficiently well designed so that they will thoroughly release functioning NK cells. Compared to hematological malignancies, the application of many potential NK cell-based therapies in glioma lags far behind. Here, we review several issues of NK cells and propose several strategies that will improve the efficacy of NK cell-based cancer immunotherapy in the treatment of glioma.

scholarly journals Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment

2010 ◽  
Vol 207 (10) ◽  
pp. 2065-2072 ◽  
Author(s):  
Nathalie T. Joncker ◽  
Nataliya Shifrin ◽  
Frédéric Delebecque ◽  
David H. Raulet
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Wild Type ◽  
Mhc I ◽  
Cell Functions ◽  
Histocompatibility Complex ◽  
Activating Receptors ◽  
Nk Cell Differentiation ◽  
Deficient Mice

Some mature natural killer (NK) cells cannot be inhibited by major histocompatibility complex (MHC) I molecules, either because they lack corresponding inhibitory receptors or because the host lacks the corresponding MHC I ligands for the receptors. Such NK cells nevertheless remain self-tolerant and exhibit a generalized hyporesponsiveness to stimulation through activating receptors. To address whether NK cell responsiveness is set only during the NK cell differentiation process, we transferred mature NK cells from wild-type (WT) to MHC I–deficient hosts or vice versa. Remarkably, mature responsive NK cells from WT mice became hyporesponsive after transfer to MHC I–deficient mice, whereas mature hyporesponsive NK cells from MHC I–deficient mice became responsive after transfer to WT mice. Altered responsiveness was evident among mature NK cells that had not divided in the recipient animals, indicating that the cells were mature before transfer and that alterations in activity did not require cell division. Furthermore, the percentages of NK cells expressing KLRG1, CD11b, CD27, and Ly49 receptors specific for H-2b were not markedly altered after transfer. Thus, the functional activity of mature NK cells can be reset when the cells are exposed to a changed MHC environment. These findings have important implications for how NK cell functions may be curtailed or enhanced in the context of disease.

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