This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Waldhauer, I. Articles by Steinle, A. Search for Related Content PubMed PubMed Citation Articles by Waldhauer, I. Articles by Steinle, A.

Proteolytic Release of Soluble UL16-Binding Protein 2 from Tumor Cells

Department of Immunology, Institute for Cell Biology, Eberhard-Karls University Tübingen, Tübingen, Germany

Requests for reprints: Alexander Steinle, Department of Immunology, Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle 15, D-72076 Tübingen, Germany. Phone: 49-7071-29-80992; Fax: 49-7071-29-5653; E-mail: alexander.steinle{at}uni-tuebingen.de.

The MHC class I–related ligands of the immunoreceptor NKG2D are frequently expressed by tumor cells and stimulate tumor immunity mediated by CD8 T cells and natural killer (NK) cells. In humans, NKG2D ligands (NKG2DL) are encoded by the MHC-encoded MIC and non–MHC-encoded UL16-binding protein (ULBP) families of proteins. Recently, we and others showed that tumor cells release soluble MICA (sMICA), thereby counteracting NKG2D-mediated tumor immunosurveillance. Here, we now report that ULBP2 molecules are likewise released from tumor cells in a processed soluble form, and that soluble ULBP2 (sULBP2) can be detected in sera of some patients with hematopoietic malignancies. Tumor cell–derived sULBP2 as opposed to cell-bound ULBP2 does not down-regulate NKG2D on NK cells. Unexpectedly, the glycosylphosphatidylinositol-anchored ULBP2 molecules are not released by phospholipases but by the action of metalloproteases. Proteolytic shedding of both NKG2D ligands MICA and ULBP2 by tumor cells was strongly enhanced after phorbol 12-myristate 13-acetate treatment and paralleled by a markedly reduced susceptibility to NKG2D-mediated cytotoxicity. Shedding of MICA and ULBP2 can be blocked by the same inhibitors, suggesting the involvement of related metalloproteases. Thus, our data suggest that reducing NKG2DL surface densities is due to a common cleavage process executed by metalloproteases that promotes escape of tumors from NKG2D-mediated immunosurveillance. (Cancer Res 2006; 66(5): 2520-6)

This article has been cited by other articles:

				I. Waldhauer, D. Goehlsdorf, F. Gieseke, T. Weinschenk, M. Wittenbrink, A. Ludwig, S. Stevanovic, H.-G. Rammensee, and A. Steinle Tumor-Associated MICA Is Shed by ADAM Proteases Cancer Res., August 1, 2008; 68(15): 6368 - 6376. [Abstract] [Full Text] [PDF]

				W. Cao, X. Xi, Z. Wang, L. Dong, Z. Hao, L. Cui, C. Ma, and W. He Four novel ULBP splice variants are ligands for human NKG2D Int. Immunol., August 1, 2008; 20(8): 981 - 991. [Abstract] [Full Text] [PDF]

				B. Le Maux Chansac, D. Misse, C. Richon, I. Vergnon, M. Kubin, J.-C. Soria, A. Moretta, S. Chouaib, and F. Mami-Chouaib Potentiation of NK cell-mediated cytotoxicity in human lung adenocarcinoma: role of NKG2D-dependent pathway Int. Immunol., July 1, 2008; 20(7): 801 - 810. [Abstract] [Full Text] [PDF]

				D. R. Siemens, N. Hu, A. K. Sheikhi, E. Chung, L. J. Frederiksen, H. Pross, and C. H. Graham Hypoxia Increases Tumor Cell Shedding of MHC Class I Chain-Related Molecule: Role of Nitric Oxide Cancer Res., June 15, 2008; 68(12): 4746 - 4753. [Abstract] [Full Text] [PDF]

				A. Clayton, J. P. Mitchell, J. Court, S. Linnane, M. D. Mason, and Z. Tabi Human Tumor-Derived Exosomes Down-Modulate NKG2D Expression J. Immunol., June 1, 2008; 180(11): 7249 - 7258. [Abstract] [Full Text] [PDF]

				S. Armeanu, M. Krusch, K. M. Baltz, T. S. Weiss, I. Smirnow, A. Steinle, U. M. Lauer, M. Bitzer, and H. R. Salih Direct and Natural Killer Cell-Mediated Antitumor Effects of Low-Dose Bortezomib in Hepatocellular Carcinoma Clin. Cancer Res., June 1, 2008; 14(11): 3520 - 3528. [Abstract] [Full Text] [PDF]

				S. Diermayr, H. Himmelreich, B. Durovic, A. Mathys-Schneeberger, U. Siegler, U. Langenkamp, J. Hofsteenge, A. Gratwohl, A. Tichelli, M. Paluszewska, et al. NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities Blood, February 1, 2008; 111(3): 1428 - 1436. [Abstract] [Full Text] [PDF]

				C. Maccalli, D. Nonaka, A. Piris, D. Pende, L. Rivoltini, C. Castelli, and G. Parmiani NKG2D-Mediated Antitumor Activity by Tumor-Infiltrating Lymphocytes and Antigen-Specific T-Cell Clones Isolated from Melanoma Patients Clin. Cancer Res., December 15, 2007; 13(24): 7459 - 7468. [Abstract] [Full Text] [PDF]

				G. Porcu-Buisson, M. Lambert, L. Lyonnet, A. Loundou, M. Gamerre, L. Camoin-Jau, F. Dignat-George, S. Caillat-Zucman, and P. Paul Soluble MHC Class I chain-related molecule serum levels are predictive markers of implantation failure and successful term pregnancies following IVF Hum. Reprod., August 1, 2007; 22(8): 2261 - 2266. [Abstract] [Full Text] [PDF]

				W. Cao, X. Xi, Z. Hao, W. Li, Y. Kong, L. Cui, C. Ma, D. Ba, and W. He RAET1E2, a Soluble Isoform of the UL16-binding Protein RAET1E Produced by Tumor Cells, Inhibits NKG2D-mediated NK Cytotoxicity J. Biol. Chem., June 29, 2007; 282(26): 18922 - 18928. [Abstract] [Full Text] [PDF]

				P. Roda-Navarro and H. T. Reyburn Intercellular protein transfer at the NK cell immune synapse: mechanisms and physiological significance FASEB J, June 1, 2007; 21(8): 1636 - 1646. [Abstract] [Full Text] [PDF]

				N. Suciu-Foca, N. Feirt, Q.-Y. Zhang, G. Vlad, Z. Liu, H. Lin, C.-C. Chang, E. K. Ho, A. I. Colovai, H. Kaufman, et al. Soluble Ig-Like Transcript 3 Inhibits Tumor Allograft Rejection in Humanized SCID Mice and T Cell Responses in Cancer Patients J. Immunol., June 1, 2007; 178(11): 7432 - 7441. [Abstract] [Full Text] [PDF]

				A. Lopez-Soto, A. Quinones-Lombrana, R. Lopez-Arbesu, C. Lopez-Larrea, and S. Gonzalez Transcriptional Regulation of ULBP1, a Human Ligand of the NKG2D Receptor J. Biol. Chem., October 13, 2006; 281(41): 30419 - 30430. [Abstract] [Full Text] [PDF]

				J. Spreu, T. Stehle, and A. Steinle Human Cytomegalovirus-Encoded UL16 Discriminates MIC Molecules by Their {alpha}2 Domains. J. Immunol., September 1, 2006; 177(5): 3143 - 3149. [Abstract] [Full Text] [PDF]

				G. Eisele, J. Wischhusen, M. Mittelbronn, R. Meyermann, I. Waldhauer, A. Steinle, M. Weller, and M. A. Friese TGF-{beta} and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells Brain, September 1, 2006; 129(9): 2416 - 2425. [Abstract] [Full Text] [PDF]