scholarly journals Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell–driven tumor immunity

Science ◽  
2018 ◽  
Vol 359 (6383) ◽  
pp. 1537-1542 ◽  
Author(s):  
Lucas Ferrari de Andrade ◽  
Rong En Tay ◽  
Deng Pan ◽  
Adrienne M. Luoma ◽  
Yoshinaga Ito ◽  
...  
Keyword(s):  
Natural Killer ◽  
Antitumor Immunity ◽  
Nk Cell ◽  
Human Cancer ◽  
Receptor Activation ◽  
Cytotoxic Lymphocytes ◽  
Immune Recognition ◽  
Humanized Mouse Model ◽  
Human Cancers ◽  
Proteolytic Shedding

MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.

scholarly journals Immune-Tumor Interactions in Resistance to Cancer Immunotherapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-45-SCI-45
Author(s):  
Kai W. Wucherpfennig
Keyword(s):  
Research Funding ◽  
Human Cancer ◽  
Receptor Activation ◽  
Cytotoxic Lymphocytes ◽  
Immune Recognition ◽  
Humanized Mouse Model ◽  
Human Cancer Cells ◽  
Human Cancers ◽  
Novel Approach ◽  
Proteolytic Shedding

MICA and MICB (MICA/B) are expressed by many human cancers due to cellular stress and tag cells for elimination by cytotoxic lymphocytes through NKG2D receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA/B proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA/B by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and also reduced human melanoma metastases in a humanized mouse model. Anti-tumor immunity was mediated mainly by NK cells through activation of NKG2D and CD16 Fc receptors. This novel approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity. Disclosures Wucherpfennig: BMS: Research Funding; Novartis: Research Funding; TCR2: Consultancy; Tscan: Consultancy.

scholarly journals The fatty-acid amide hydrolase inhibitor URB597 inhibits MICA/B shedding

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kazuma Sekiba ◽  
Motoyuki Otsuka ◽  
Takahiro Seimiya ◽  
Eri Tanaka ◽  
Kazuyoshi Funato ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cancer Cells ◽  
Fatty Acid Amide Hydrolase ◽  
Human Cancer ◽  
Acid Amide ◽  
Cytotoxic Lymphocytes ◽  
Immune Recognition ◽  
Stressed Cells ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Abstract MICA/B proteins are expressed on the surface of various types of stressed cells, including cancer cells. Cytotoxic lymphocytes expressing natural killer group 2D (NKG2D) receptor recognize MICA/B and eliminate the cells. However, cancer cells evade such immune recognition by inducing proteolytic shedding of MICA/B proteins. Therefore, preventing the shedding of MICA/B proteins could enhance antitumor immunity. Here, by screening a protease inhibitor library, we found that the fatty-acid amide hydrolase (FAAH) inhibitor, URB597, suppresses the shedding of MICA/B. URB597 significantly reduced the soluble MICA level in culture medium and increased the MICA level on the surface of cancer cells. The effect was indirect, being mediated by increased expression of tissue inhibitor of metalloproteinases 3 (TIMP3). Knockdown of TIMP3 expression reversed the effect of URB597, confirming that TIMP3 is required for the MICA shedding inhibition by URB597. In contrast, FAAH overexpression reduced TIMP3 expression and the cell-surface MICA level and increased the soluble MICA level. These results suggest that inhibition of FAAH could prevent human cancer cell evasion of immune-mediated clearance.

scholarly journals The Src Family Tyrosine Kinase Fyn Regulates Natural Killer T Cell Development

1999 ◽  
Vol 190 (8) ◽  
pp. 1189-1196 ◽  
Author(s):  
Paul Gadue ◽  
Neil Morton ◽  
Paul L. Stein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Nk Cell ◽  
T Cell Development ◽  
Receptor Activation ◽  
Cell Development ◽  
T Cell Subsets ◽  
Nk T Cells ◽  
Nk T Cell

T lymphocytes express two Src tyrosine kinases, Lck and Fyn. While thymocyte and T cell subsets are largely normal in fyn−/− mice, animals lacking Lck have impaired T cell development. Here, it is shown that Fyn is required for the rapid burst of interleukin (IL)-4 and IL-13 synthesis, which occurs promptly after T cell receptor activation. The lack of cytokine induction in fyn mutant mice is due to a block in natural killer (NK) T cell development. Studies using bone marrow chimeras indicate that the defect behaves in a cell-autonomous manner, and the lack of NK T cells is probably not caused by inappropriate microenvironmental cues. Both NK T cells and conventional T cells express similar levels of Lck, implying that Fyn and Lck have distinct roles in regulating NK T cell ontogeny. The fyn mutation defines the first signaling molecule that is selectively required for NK T cell, but not for T lymphocyte or NK cell development.

scholarly journals ATP secreted by endothelial cells blocks CX3CL1-elicited natural killer cell chemotaxis and cytotoxicity via P2Y11 receptor activation

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4492-4500 ◽  
Author(s):  
Stefania Gorini ◽  
Giulia Callegari ◽  
Giulia Romagnoli ◽  
Caterina Mammi ◽  
Domenico Mavilio ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Vascular Injury ◽  
Nk Cell ◽  
Umbilical Vein ◽  
Killer Cell ◽  
Receptor Activation ◽  
Human Coronary Artery ◽  
Uridine Triphosphate

Abstract Endothelial cells (ECs) represent a major source of actively secreted adenosine triphosphate (ATP). Natural killer (NK) cells can mediate vascular injury in several pathologic conditions, including cytomegalovirus infection and vascular leak syndrome. We studied NK-cell expression of P2 receptors and the role of these nucleotide receptors in the regulation of endothelial-NK cell cross-talk. NK cells from healthy subjects expressed P2Y1,2,4,6,11,12,13,14 and P2X1,4,5,6,7 receptors. NK cells stimulated with ATP, but not uridine triphosphate, increased intracellular Ca2+ and chemokinesis. Moreover, ATP, but not uridine triphosphate, inhibited NK chemotaxis in response to CX3CL1, whereas chemotaxis to CXCL12 was increased. CX3CL1 elicited killing of human umbilical vein ECs and human coronary artery ECs by NK cells. However, in the presence of ATP, CX3CL1 failed to stimulate killing of ECs. Such inhibitory effect was lost on exogenous addition of the ATP-hydrolyzing enzyme apyrase or by pharmacologic inhibition of the P2Y11R, and correlated with increased intracellular cyclic adenosine monophosphate concentrations induced by ATP or other P2Y11R agonists, including NAD+. Extracellular ATP regulates NK-cell cytotoxicity via P2Y11R activation, protecting ECs from CX3CL1-elicited NK cell–mediated killing. These findings point out the P2Y11R as a potential target for pharmacologic intervention aimed at reducing NK-mediated vascular injury.

scholarly journals Enhanced AIS Based Intrusion Detection System Using Natural Killer Cells

2021 ◽  
Author(s):  
B. J. Bejoy ◽  
S. Janakiraman
Keyword(s):  
Intrusion Detection ◽  
Nk Cells ◽  
Natural Killer ◽  
Intrusion Detection System ◽  
Nk Cell ◽  
Detection System ◽  
Receptor Activation ◽  
Cytokine Release ◽  
Selection Algorithm ◽  
Activating Receptor

Intrusion detection system is used to monitor the system and network activities to identify anomalies and attacks so that integrity, availability, and confidentiality can be preserved. Here an intrusion detection system based on Artificial Immune System is proposed based on Natural Killer (NK) cells with immunological memory. NK cells are created and each NK cells detection radius is determined using the negative selection algorithm and is trained to detect various attacks. Effective cells with high fairness values are proliferated and distributed to the network using clonal selection algorithm. In this paper, two types of NK cell are used-a Heavyweight NK cell (HWNK) and a number of Lightweight NK cells (LWNK). The incoming data is vectorized and Major Histocompatibility Complex Class I (MHC1) is created. Then based on this MHC1, any of the receptors i.e. Activating Receptor or Inhibiting Receptor is activated. If it is the signature of an attack, Activating Receptor is activated. Activating receptor activation results in either cytokine release or apoptosis. Here cytokine release means an alarm is generated informing the administrator and apoptosis stands for dropping of the packet. If Inhibiting Receptor is activated, it’s a normal packet there is no action taken. The technique proposed yields high accuracy, better detection rate and quick response time.

scholarly journals Phospho-proteomics reveals that RSK signaling is required for proliferation of natural killer cells stimulated with IL-2 or IL-15

2021 ◽  
Author(s):  
Melanie A MacMullan ◽  
Pin Wang ◽  
Nicholas Alexander Graham
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Critical Role ◽  
Cytokine Signaling ◽  
Cytotoxic Lymphocytes ◽  
Signaling Events ◽  
Bioinformatic Approaches ◽  
Ribosomal S6 Kinase

Natural killer (NK) cells are cytotoxic lymphocytes that play a critical role in the innate immune system. Although cytokine signaling is crucial for the development, expansion, and cytotoxicity of NK cells, the signaling pathways stimulated by cytokines are not well understood. Here, we sought to compare the early signaling dynamics induced by the cytokines interleukin (IL)-2 and IL-15 using liquid chromatography-mass spectrometry (LC-MS)-based phospho-proteomics. Following stimulation of the immortalized NK cell line NK-92 with IL-2 or IL-15 for 5, 10, 15, or 30 minutes, we identified 8,692 phospho-peptides from 3,023 proteins. Comparing the kinetic profiles of 3,619 fully quantified phospho-peptides, we found that IL-2 and IL-15 induced highly similar signaling in NK-92 cells. Among the IL-2/IL-15-regulated phospho-sites were both well-known signaling events like the JAK/STAT pathway and novel signaling events with potential functional significance including LCP1 Ser5, PAK2 Ser141, and STK17B Ser12. Using bioinformatic approaches, we sought to identify kinases regulated by IL-2/IL-15 stimulation and found that the p90 ribosomal S6 kinase (p90RSK) family was activated by both cytokines. Using pharmacological inhibitors, we then discovered that RSK signaling is required for IL-2 and IL-15-induced proliferation in NK-92 cells. Taken together, our analysis represents the first phospho-proteomic characterization of cytokine signaling in NK cells and increases our understanding of how cytokine signaling regulates NK cell function.

scholarly journals Pseudomonas aeruginosa Infection Impairs NKG2D-Dependent NK Cell Cytotoxicity through Regulatory T-Cell Activation

2020 ◽  
Vol 88 (12) ◽  
Author(s):  
Mickael Vourc’h ◽  
Gaelle David ◽  
Benjamin Gaborit ◽  
Alexis Broquet ◽  
Cedric Jacqueline ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Nk Cells ◽  
Natural Killer ◽  
Antitumor Immunity ◽  
Nk Cell ◽  
Dependent Manner ◽  
Cell Cytotoxicity ◽  
Content Type ◽  
Cytotoxic Response ◽  
Nk Cell Cytotoxicity

ABSTRACT Natural killer (NK) cells play a key role in both antibacterial and antitumor immunity. Pseudomonas aeruginosa infection has already been reported to alter NK cell functions. We studied in vitro the effect of P. aeruginosa on NK cell cytotoxic response (CD107a membrane expression) to a lymphoma cell line. Through positive and negative cell sorting and adoptive transfer, we determined the influence of monocytes, lymphocytes, and regulatory T cells (Treg) on NK cell function during P. aeruginosa infection. We also studied the role of the activating receptor natural killer group 2D (NKG2D) in NK cell response to B221. We determined that P. aeruginosa significantly altered both cytotoxic response to B221 and NKG2D expression on NK cells in a Treg-dependent manner and that the NKG2D receptor was involved in NK cell cytotoxic response to B221. Our results also suggested that during P. aeruginosa infection, monocytes participated in Treg-mediated NK cell alteration. In conclusion, P. aeruginosa infection impairs NK cell cytotoxicity and alters antitumor immunity. These results highlight the strong interaction between bacterial infection and immunity against cancer.

scholarly journals Effects of β-adrenergic receptor activation, cholera toxin and forskolin on human natural killer cell function

1990 ◽  
Vol 272 (2) ◽  
pp. 327-331 ◽  
Author(s):  
M M Whalen ◽  
A D Bankhurst
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cholera Toxin ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
K562 Cells ◽  
Receptor Activation ◽  
Tumour Cells ◽  
Human Natural Killer Cell

Membranes from highly purified natural killer (NK) cells were ADP-ribosylated by treatment with cholera toxin (CTX). CTX resulted in a single band of specific 32P incorporation at Mr 43,600. CTX treatment of intact NK cells caused a 9-fold increase in cyclic AMP (cAMP) concentrations. Pretreatment of NK cells with CTX diminished their ability to lyse K562 tumour cells by up to 79%. Forskolin treatment elevated NK cell cAMP levels 8-fold and decreased lysis of K562 cells by up to 45%. Adrenaline and isoprenaline (isoproterenol) both inhibited lysis of K562 cells by approx. 35% and elevated cAMP by at least 2.5-fold, and their inhibition of lysis was reversed by propranolol. These data suggest that the stimulatory guanine-nucleotide-binding protein GS coupled to beta-adrenergic receptors is involved in transducing signals which inhibit NK cell lysis of tumour cells. CTX and forskolin also diminish the ability of NK cells to bind K562 cells (binding is necessary for lysis). This suggests that the NK-cell receptor(s) for the tumour cell may be altered as a consequence of cAMP-mediated events or by activation of GS.

scholarly journals Transmission of Toxoplasma gondii from Infected Dendritic Cells to Natural Killer Cells

2009 ◽  
Vol 77 (3) ◽  
pp. 970-976 ◽  
Author(s):  
Catrine M. Persson ◽  
Henrik Lambert ◽  
Polya P. Vutova ◽  
Isabel Dellacasa-Lindberg ◽  
Joanna Nederby ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Immune Recognition ◽  
Cell Infection ◽  
Obligate Intracellular ◽  
Rapid Transfer ◽  
Intraperitoneal Inoculation

ABSTRACT The obligate intracellular parasite Toxoplasma gondii can actively infect any nucleated cell type, including cells from the immune system. In the present study, we observed that a large number of natural killer (NK) cells were infected by T. gondii early after intraperitoneal inoculation of parasites into C57BL/6 mice. Interestingly, one mechanism of NK cell infection involved NK cell-mediated targeting of infected dendritic cells (DC). Perforin-dependent killing of infected DC led to active egress of infectious parasites that rapidly infected adjacent effector NK cells. Infected NK cells were not efficiently targeted by other NK cells. These results suggest that rapid transfer of T. gondii from infected DC to effector NK cells may contribute to the parasite's sequestration and shielding from immune recognition shortly after infection.

scholarly journals Perforin gene mutations in patients with acquired aplastic anemia

Blood ◽  
2007 ◽  
Vol 109 (12) ◽  
pp. 5234-5237 ◽  
Author(s):  
Elena E. Solomou ◽  
Federica Gibellini ◽  
Brian Stewart ◽  
Daniela Malide ◽  
Maria Berg ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Aplastic Anemia ◽  
Natural Killer ◽  
Nk Cell ◽  
Bone Marrow Failure ◽  
Genetic Alterations ◽  
Cytotoxic Lymphocytes ◽  
Activated T Cells ◽  
Hematopoietic Stem

Abstract Perforin is a cytolytic protein expressed mainly in activated cytotoxic lymphocytes and natural killer cells. Inherited perforin mutations account for 20% to 40% of familial hemophagocytic lymphohistiocytosis, a fatal disease of early childhood characterized by the absence of functional perforin. Aplastic anemia, the paradigm of immune-mediated bone marrow failure syndromes, is characterized by hematopoietic stem cell destruction by activated T cells and Th1 cytokines. We examined whether mutations in the perforin gene occurred in acquired aplastic anemia. Three nonsynonymous PRF1 mutations among 5 unrelated patients were observed. Four of 5 patients with the mutations showed some hemophagocytosis in the bone marrow at diagnosis. Perforin protein levels in these patients were very low or absent, and perforin granules were completely absent. Natural killer (NK) cell cytotoxicity from these patients was significantly decreased. Our data suggest that PRF1 genetic alterations help explain the aberrant proliferation and activation of cytotoxic T cells and may represent genetic risk factors for bone marrow failure.

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