Neutralization of tumor-derived soluble Glucocorticoid-Induced TNFR-Related Protein (GITR) ligand increases NK cell anti-tumor reactivity

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Blood First Edition Paper, prepublished online August 8, 2008; DOI

10.1182/blood-2008-03-143016.

Neutralization of tumor-derived soluble Glucocorticoid-Induced TNFR-Related

Protein (GITR) ligand increases NK cell anti-tumor reactivity

Katrin Miriam Baltz, Matthias Krusch, Tina Baessler, Joachim Schmiedel,

Anita Bringmann, Brossart, and Helmut Rainer Salih*

Department of Hematology and Oncology, University of Tuebingen, Tuebingen,

Germany

Department of Hematology and Oncology, University of Bonn, Bonn, Germany

* Corresponding author; email: helmut.salih@... .

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

fusionprotein. While 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 employed to improve immunotherapeutic

strategies relying on NK cell reactivity.