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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3735-3743. Prepublished online as a Blood First Edition Paper on August 8, 2008; DOI 10.1182/blood-2008-03-143016. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-03-143016v1 112/9/3735    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Baltz, K. M. Articles by Salih, H. R. Search for Related Content PubMed PubMed Citation Articles by Baltz, K. M. Articles by Salih, H. R. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Neutralization of tumor-derived soluble Glucocorticoid-Induced TNFR-Related Protein ligand increases NK cell anti-tumor reactivity Katrin M. Baltz1,*, Matthias Krusch1,*, Tina Baessler1,*, Benjamin J. Schmiedel1, Anita Bringmann1,2, Peter Brossart1,2, and Helmut R. Salih1 1 Department of Hematology and Oncology, University of Tuebingen, Tuebingen; and 2 Department of Hematology and Oncology, University of Bonn, Bonn, Germany NK cell anti-tumor reactivity is governed by a balance of activating and inhibitory receptors including various TNF receptor (TNFR) family members. Here we report that human tumor cells release a soluble form of the TNF family member Glucocorticoid-Induced TNFR-Related Protein (GITR) ligand (sGITRL), which can be detected in cell culture supernatants. Tumor-derived sGITRL concentration-dependently reduced NK cell cytotoxicity and IFN- production, which could be overcome by neutralization of sGITRL using a GITR-Ig fusion protein. Although sGITRL did not induce apoptosis in NK cells, it diminished nuclear localized RelB, indicating that sGITRL negatively modulates NK cell NF-B activity. Furthermore, we detected substantial levels of sGITRL in sera of patients with various malignancies, but not in healthy controls. Presence of sGITRL-containing patient serum in cocultures with tumor cells significantly reduced NK cell cytotoxicity and IFN- production, which could again be restored by neutralization of sGITRL. The strong correlation of tumor incidence and elevated sGITRL levels indicates that sGITRL is released from cancers in vivo, leading to impaired NK cell immunosurveillance of human tumors. Our data suggest that determination of sGITRL levels might be implemented as a tumor marker in patients, and GITRL neutralization may be used to improve immunotherapeutic strategies relying on NK cell reactivity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Baessler, M. Krusch, B. J. Schmiedel, M. Kloss, K. M. Baltz, A. Wacker, H. M. Schmetzer, and H. R. Salih Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Related Protein Ligand Subverts Immunosurveillance of Acute Myeloid Leukemia in Humans Cancer Res., February 1, 2009; 69(3): 1037 - 1045. [Abstract] [Full Text] [PDF]

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