Neutralization of tumor-derived soluble glucocorticoid-induced TNFR-related protein ligand increases NK cell anti-tumor reactivity.

Abstract

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-gamma 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-kappaB 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-gamma 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.

• Authors: Katrin M Baltz, Matthias Krusch, Tina Baessler, Benjamin J Schmiedel, Anita Bringmann, Peter Brossart, Helmut R Salih
• Journal: Blood (Blood) Vol. 112 Issue 9 Pg. 3735-43 (Nov 01 2008) ISSN: 1528-0020 [Electronic] United States
• PMID: 18689545 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• NF-kappa B
• TNFSF18 protein, human
• Tumor Necrosis Factor Inhibitors
• Tumor Necrosis Factors
• Interferon-gamma

Topics

• Biomarkers, Tumor (antagonists & inhibitors, blood, metabolism)
• Cell Line, Tumor
• Coculture Techniques
• Cytotoxicity, Immunologic
• Hematologic Neoplasms (blood, immunology)
• Humans
• Interferon-gamma (biosynthesis)
• Killer Cells, Natural (immunology, metabolism)
• NF-kappa B (metabolism)
• Neoplasms (immunology, metabolism)
• Neutralization Tests
• Solubility
• Tumor Necrosis Factor Inhibitors
• Tumor Necrosis Factors (blood, metabolism)