Soluble MICB in malignant diseases: analysis of diagnostic significance and correlation with soluble MICA

Holdenrieder, Stefan; Stieber, P.; Peterfi, Andrea; Nagel, Dorothea; Steinle, Alexander; Salih, Helmut R.

doi:10.1007/s00262-006-0167-1

Cited by 110 publications

(101 citation statements)

References 24 publications

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“…Elevated levels of soluble MICA have been detected in the sera of patients suffering from various types of cancer and often correlate with a poor prognosis for the patient (48). This relationship is likely to be related to the known effects of MICA/B FIGURE 7.…”

Section: Discussionmentioning

confidence: 99%

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

Fernández-Messina

Ashiru

Boutet

et al. 2010

Journal of Biological Chemistry

143

166

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Tumor cells release NKG2D ligands to evade NKG2D-mediated immune surveillance. The purpose of our investigation was to explore the cellular mechanisms of release used by various members of the ULBP family. Using biochemical and cellular approaches in both transfectant systems and tumor cell lines, this paper shows that ULBP1, ULBP2, and ULBP3 are released from cells with different kinetics and by distinct mechanisms. Whereas ULBP2 is mainly shed by metalloproteases, ULBP3 is abundantly released as part of membrane vesicles known as exosomes. Interestingly, exosomal ULBP3 protein is much more potent for down-modulation of the NKG2D receptor than soluble ULBP2 protein. This is the first report showing functionally relevant differences in the biochemistry of the three members of the ULBP family and confirms that in depth study of the biochemical features of individual NKG2D ligands will be necessary to understand and manipulate the biology of these proteins for therapy.NKG2D is an activating immune receptor that can be expressed by most cytotoxic lymphocytes, including NK and CD8ϩ T cells (1). Engagement of NKG2D by its ligands leads to the activation or co-stimulation of lysis and cytokine secretion (for review, see Ref. 2). In humans, NKG2D ligands (NKG2D-L) 5 occur in two families of proteins: the polymorphic family of MHC-I-related chain A/B (MICA/B) and the multigene family of UL16-binding proteins (ULBPs, also known as RAET1A-E). In total, 10 members of this gene family have been described, of which six can be expressed as functional proteins (3). Two members of the ULBP family have a transmembrane region (ULBP4 and -5), like MICA/B, whereas the other ULBP molecules are linked to the cell membrane via glycosylphosphatidylinositol (GPI) anchors. The existence of such a large number of ligands for a single receptor is not fully understood but may reflect a differential role for different ligands in immune surveillance or an evolutionary response to selective pressures exerted by pathogens or cancer.In general, NKG2D-L are not expressed ubiquitously; instead, they are expressed in response to several types of cellular stress, such as pathogen infection (4), DNA damage (5), proteasome inhibition (6), and tumor transformation (7). For example, MICA/B are expressed in epithelial tumors, melanoma, neuroblastoma, various hematopoietic malignancies, and carcinomas; ULBPs are found in leukemia, gliomas and melanomas. An additional complication is that mRNA can be found in many cells that do not express protein suggesting post-transcriptional regulation of NKG2D-L expression (8 -10).Mice deficient in NKG2D expression show an enhanced susceptibility to the development of tumors (11). However, shedding NKG2D-L as soluble molecules allows tumor cells to evade NKG2D surveillance. Apart from reducing NKG2D-L expression on the tumor cell surface, the release of soluble molecules may also impair immune surveillance by promoting down-regulation of NKG2D (12, 13). In fact, the sustained presence in vivo of NKG2D-L down-modulates...

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Section: Discussionmentioning

confidence: 99%

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

Fernández-Messina

Ashiru

Boutet

et al. 2010

Journal of Biological Chemistry

143

166

View full text Add to dashboard Cite

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“…Indeed, soluble forms of NKG2DLs are present in the serum of cancer patients, and their levels correlate with tumor stage and metastasis (12,20,21,(38)(39)(40)(41), as well as with reduced expression of NKG2D on NK cells and other cytotoxic lymphocytes (11,21,42).…”

Section: Discussionmentioning

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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“…22,24,29 For MM, sMICA is described as an independent prognostic marker for OS and progression-free survival. 22,24,29 This study clearly shows Soluble NKG2D ligands in chronic lymphocytic leukemia H Nückel et al that sULBP2 rather than sMICA or sMICB is of prognostic relevance for disease progression and OS of CLL patient. Moreover, we were able to identify sULBP2 but not sMICA or sMICB as a new independent prognostic marker for disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…Elevated levels of sNKG2DL are correlated with metastasis, advanced disease stage, and poor prognosis. 12,[20][21][22][24][25][26][27][28] Soluble MICA (sMICA) is reported to be an independent prognostic factor for the overall and progression-free survival in multiple myeloma (MM) patients. Elevated sMICA levels seem to be associated with an enhanced risk of disease progression in MM patients with disease stage I.…”

Section: Introductionmentioning

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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Soluble MICB in malignant diseases: analysis of diagnostic significance and correlation with soluble MICA

Cited by 110 publications

References 24 publications

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

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

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

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