Natural Killer Cell Cytotoxicity Is Suppressed by Exposure to the Human NKG2D Ligand MICA*008 That Is Shed by Tumor Cells in Exosomes

Ashiru, Omodele; Boutet, Philippe; Fernández-Messina, Lola; Agüera-González, Sonia; Skepper, Jeremy N.; Valés‐Gómez, Mar; Reyburn, Hugh

doi:10.1158/0008-5472.can-09-1688

Cited by 357 publications

(370 citation statements)

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“…Exosomes from tumors cells harbor NKG2D ligand such as MICA*008 or ULBP3 proteins, which suppress Natural Killer cell toxicity [93]. Ligation of NKG2D with its ligands led to a down regulation of NKG2D expression.…”

Section: Tumor Promoter Activitymentioning

confidence: 99%

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Exosomes as intercellular signalosomes and pharmacological effectors

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Silvente-Poirot

et al. 2011

Biochemical Pharmacology

473

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International audienceCell secretion is a general process involved in various biological responses. Exosomes are part of this process and have gained considerable scientific interest in the past five years. Several steps through investigations across the last 20years can explain this interest. First characterized during reticulocyte maturation, they were next characterized as a key player in the immune response and cancer immunotherapy. More recently they were characterized as vectors of mRNAs, miRNAs and also lipid mediators able to act on target cells. They are the only type of vesicles released from an intracellular compartment from cells in viable conditions. They appear as a vectorized signaling system operating from inside a donor cell towards either the periphery, the cytosol, or possibly to the nucleus of target cells. Exosomes from normal cells trigger positive effects, whereas those from pathological ones, such as tumor cells or infected ones may trigger non-positive health effects. Therefore regulating the biogenesis and secretion of exosomes appear as a pharmacological challenge to intervene in various pathophysiologies. Exosome biogenesis and molecular content, interaction with target cells, utilisation as biomarkers, and functional effects in various pathophysiologies are considered in this review

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Section: Tumor Promoter Activitymentioning

confidence: 99%

“…Exosomes from tumors cells harbor NKG2D ligand such as MICA*008 or ULBP3 proteins, which suppress Natural Killer cell toxicity [93]. They are also enriched in an immunosuppressive lipid, the prostaglandin E2 (PGE2) [9] which interacts with a family of four GPCR (EP1 to EP4).…”

Section: E Pharmacology Of Exosomes: the Future Challengementioning

confidence: 99%

Exosomes as intercellular signalosomes and pharmacological effectors

Record

Subra

Silvente-Poirot

et al. 2011

Biochemical Pharmacology

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336

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“…The notion that different MIC alleles exhibit distinct molecular structures and different shedding modalities (14,31) prompted us to examine whether the chemotherapeutic agents could differentially affect the release of distinct MICA alleles. To this end, the MM cell line LP1, which does not express endogenous MICA and MICB, was stably transduced with cDNA encoding MICA*008 (carrying a truncated cytoplasmic tail and released by exosomes or through exocytosis), MICA*019 (which represents the prototype of the long form of MICA alleles), or MICB and exposed to DOX treatment.…”

Section: Drug Treatment Of MM Cells Selectively Affects the Release Omentioning

confidence: 99%

“…Another level of complexity is reflected by the fact that MICA displays a high degree of polymorphism leading to an allele-dependent shedding, as demonstrated for the allelic variant MICA*008 released in association with exosomes (14).…”

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confidence: 99%

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Zingoni

Cecere

Vulpis

et al. 2015

The Journal of Immunology

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Genotoxic stress can promote antitumor NK cell responses by upregulating the surface expression of activating ligands on cancer cells. Moreover, a number of studies suggested a role for soluble NK group 2D ligands in the impairment of NK cell tumor recognition and killing. We investigated whether genotoxic stress could promote the release of NK group 2D ligands (MHC class I-related chain [MIC]A and MICB), as well as the molecular mechanisms underlying this event in human multiple myeloma (MM) cells. Our results show that genotoxic agents used in the therapy of MM (i.e., doxorubicin and melphalan) selectively affect the shedding of MIC molecules that are sensitive to proteolytic cleavage, whereas the release of the short MICA*008 allele, which is frequent in the white population, is not perturbed. In addition, we found that a disintegrin and metalloproteinase 10 expression is upregulated upon chemotherapeutic treatment both in patient-derived CD138(+)/CD38(+) plasma cells and in several MM cell lines, and we demonstrate a crucial role for this sheddase in the proteolytic cleavage of MIC by means of silencing and pharmacological inhibition. Interestingly, the drug-induced upregulation of a disintegrin and metalloproteinase 10 on MM cells is associated with a senescent phenotype and requires generation of reactive oxygen species. Moreover, the combined use of chemotherapeutic drugs and metalloproteinase inhibitors enhances NK cell-mediated recognition of MM cells, preserving MIC molecules on the cell surface and suggesting that targeting of metalloproteinases in conjunction with chemotherapy could be exploited for NK cell-based immunotherapeutic approaches, thus contributing to avoid the escape of malignant cells from stress-elicited immune responses

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“…In addition, NKG2D ligands may be secreted via exosomes maintaining their ability to modulate NKG2D cell surface levels [12]. Cancer-derived exosomes may downregulate receptor expression and reduce NK and CD8 + T cells functional responses, as reported recently [13,14]. Thus, the NKG2D recognition system has been postulated as a relevant mechanism in the immune response to cancer or in the tumor evasion from immunosurveillance [15,16].…”

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confidence: 95%

Wiskott‐Aldrich syndrome protein (WASp) and N‐WASp are involved in the regulation of NK‐cell migration upon NKG2D activation

2012

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NKG2D is a transmembrane receptor mainly expressed on CD8 + T cells and NK cells. Engagement of NKG2D with its ligands can trigger a cytotoxic response. It has beenshown that tumor cells deliver soluble NKG2D ligands as a mechanism of immune evasion through the downregulation of surface-expressed NKG2D. These ligands may be also secreted in microvesicles and regulate NK-cell function, but the existence of alternative mechanisms has not been explored. In this study, we describe that NKG2D activation inhibits NK-cell chemotaxis toward a CXCL12 gradient. Costimulation of the inhibitory receptor NKG2A rescues NK-cell migration rates. Thus, the balance of NKG2D/NKG2A activation may determine the migratory ability of NK cells. Furthermore, our data indicated that NKG2D cross-linking induces the activation of the Rho GTPases Rac1 and Cdc42, while RhoA activity is decreased. Pharmacological inhibition of the Cdc42 effectors Wiskott-Aldrich syndrome protein (WASp)/N-WASp, and the reduction of their levels using RNA interference partially abolished NKG2D-mediated impairment of cell migration, suggesting a pivotal role of Cdc42 in the regulation of NK-cell migration by NKG2D activation. Therefore, our results provide a new mechanism that may contribute to the immune response or evasion in tumors.Keywords: Chemotaxis r Migration r NKG2D r Rho GTPases r WASp Introduction NK cells are the first host defense against viral infections and tumors. Degranulation and secretion of cytokines and cytotoxic molecules are the main NK-cell functions. The outcome of NKcell activity is regulated by a balance between activating and inhibitory signals delivered by a repertoire of surface receptors. In human NK cells, these receptors may be classified in killer cell immunoglobulin-like receptors (KIR), natural cytotoxic receptors (NCRs), or C-type lectin receptors [1][2][3]. NKG2D is a C-type lectin Correspondence: Dr. Carlos López-Larrea e-mail: inmuno@hca.es activating receptor which is expressed not only in NK cells, acting as an activating receptor itself, but also in γδ T, CD8 + αβ T lymphocytes and NKT cells in humans, where it acts as a costimulatory molecule [4,5].In humans, the ligands for NKG2D (NKG2DL) are major histocompatibility class I-related chain A/B (MICA/B) and UL-16 binding proteins 1-5 (ULBP1-5) [6]. NKG2D surface levels are regulated by these ligands. In fact, NKG2DL expression may result in immune activation or immune evasion. Although ligand expression is normally restricted under physiological conditions, * These authors have equally contributed to this work.www.eji-journal.eu Eur. J. Immunol. 2012. 42: 2142-2151 Leukocyte signaling 2143it is increased in a broad variety of malignant diseases. High expression of MICA and ULBP2 is detected in ovarian cancer tissue and related to a poor prognosis [7]. Expression of NKG2DL on the cell surface of leukemia cells has also been described [8]. Furthermore, it has been described that the soluble forms of NKG2DL may be released from tumor cells [9,10] and that elevated levels a...

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Natural Killer Cell Cytotoxicity Is Suppressed by Exposure to the Human NKG2D Ligand MICA*008 That Is Shed by Tumor Cells in Exosomes

Cited by 357 publications

References 49 publications

Exosomes as intercellular signalosomes and pharmacological effectors

Exosomes as intercellular signalosomes and pharmacological effectors

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Wiskott‐Aldrich syndrome protein (WASp) and N‐WASp are involved in the regulation of NK‐cell migration upon NKG2D activation

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