Differential Clinical Significance of Individual NKG2D Ligands in Melanoma: Soluble ULBP2 as an Indicator of Poor Prognosis Superior to S100B

Paschen, Annette; Sucker, Antje; Hill, Bettina; Moll, Iris; Zapatka, Marc; Nguyen, Xuan Duc; Sim, Geok Choo; Gutmann, Isabelle; Hassel, Jessica C.; Becker, Jürgen C.; Steinle, Alexander; Schadendorf, Dirk; Ugurel, Selma

doi:10.1158/1078-0432.ccr-09-0886

Cited by 169 publications

(164 citation statements)

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“…Identification of additional models insensitive to pan-HER inhibitors such as AZD8931, yet sensitive to MEDI3622, should prove to be fertile grounds for these efforts in conjunction with proteomic studies to identify novel ADAM17 substrates in these models. It is noteworthy that ligands which are immunosuppressive upon shedding, such as ULBP2 (39) and MICA (40), were among the proteomics hits in the OE21 model (Table 3) and H358 lung cancer cells (Supplementary Table S3). MEDI3622-mediated inhibition of circulating levels of these ligands has the potential to restore CD8 þ T-cell and NK cell function.…”

Section: Discussionmentioning

confidence: 99%

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Rios-Doria¹,

Sabol²,

Chesebrough³

et al. 2015

Molecular Cancer Therapeutics

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ADAM17 is the primary sheddase for HER pathway ligands. We report the discovery of a potent and specific ADAM17 inhibitory antibody, MEDI3622, which induces tumor regression or stasis in many EGFR-dependent tumor models. The inhibitory activity of MEDI3622 correlated with EGFR activity both in a series of tumor models across several indications as well in as a focused set of head and neck patient-derived xenograft models. The antitumor activity of MEDI3622 was superior to that of EGFR/HER pathway inhibitors in the OE21 esophageal model and the COLO205 colorectal model suggesting additional activity outside of the EGFR pathway. Combination of MEDI3622 and cetuximab in the OE21 model was additive and eradicated tumors. Proteomics analysis revealed novel ADAM17 substrates that function outside of the HER pathways and may contribute toward the antitumor activity of the monoclonal antibody.

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Section: Discussionmentioning

confidence: 99%

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Rios-Doria¹,

Sabol²,

Chesebrough³

et al. 2015

Molecular Cancer Therapeutics

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“…As in our study, sULBP2 was associated as an indicator of poor prognosis superior to sMICA. 42 The functional consequences of increased sULBP2, however, remain speculative. It is reported that tumor-derived sMIC ligands impair the NKG2D receptor expression on T and NK cells.…”

Section: Discussionmentioning

confidence: 99%

The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia

et al. 2010

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Soluble or membrane-anchored ligands of NKG2D and their receptor have a critical role in the elimination of tumor cells and disease progression. Plasma samples of 98 patients with B-cell chronic lymphocytic leukemia (CLL) were analyzed with specific ELISA systems for soluble major histocompatibility complex class I-related chains (sMICA and sMICB) and UL-16-binding proteins (ULBP1, 2, and 3). The flow cytometric analysis of MICA on CLL cells and natural killer group 2 member D (NKG2D) receptors on NK cells was performed after thawing of frozen peripheral blood lymphocytes of CLL patients (N ¼ 51). Levels of sMICA, sMICB, and sULBP2 were significantly increased (Po0.001) compared with 48 controls, whereas sULBP1 3 were not detectable in patients and controls. Levels of sMICA4990 pg/ml (P ¼ 0.014), sMICB4200 pg/ml (P ¼ 0.0001), and sULBP24105 pg/ml (Po0.0001) were associated with poor treatment-free survival (TFS). Neither MICA nor NKG2D expression could be related to clinical parameters. In multivariate analysis Binet stage (P ¼ 0.002), sULBP2 (P ¼ 0.002) and ZAP-70 (P ¼ 0.002) were independent predictive factors for TFS. In patients with Binet stage A, sULBP2 levels4105 pg/ml were strongly associated (P ¼ 0.0025) with poor TFS. Our data show that soluble but not membrane-anchored NKG2D ligands or receptors are of prognostic significance in CLL. Moreover, sULBP2 seems to be useful to identify early-stage patients with risk of disease progression.

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“…Recent works have shown the remarkable role of ULBP2 as a marker for disease progression [8,21]. In addition, it has been reported that proteasome inhibitor treatment leads to a higher sensitivity to NK-cell-mediated killing by upregulation of ULBP2 expression [22], supporting its potential relevance in the development of anticancer therapy.…”

Section: Nkg2d and Nkg2a Ligation Rescues Impaired Migrationmentioning

confidence: 97%

“…This effect was abrogated by costimulation of the NKG2A receptor, while the activation of this receptor alone did not affect cell migration. These results are in keeping with the study of Culley et al [20], which describes that activating signals in NK cells, such as interaction of NKG2D with MICA promotes a stop signal to form the IS, while inhibitory signals may reverse this effect.Recent works have shown the remarkable role of ULBP2 as a marker for disease progression [8,21]. In addition, it has been reported that proteasome inhibitor treatment leads to a higher sensitivity to NK-cell-mediated killing by upregulation of ULBP2 expression [22], supporting its potential relevance in the development of anticancer therapy.…”

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confidence: 97%

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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Differential Clinical Significance of Individual NKG2D Ligands in Melanoma: Soluble ULBP2 as an Indicator of Poor Prognosis Superior to S100B

Cited by 169 publications

References 50 publications

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia

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

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