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Tumor‐derived soluble Glucocorticoid‐Induced TNF‐Related Protein (GITR) ligand diminishes anti‐tumor reactivity of NK cells
Author(s) -
Krusch Matthias,
Baltz Katrin M.,
Bringmann Anita,
Brossart Peter,
Salih Helmut R.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1079.25
Subject(s) - cancer research , chemistry , tumor necrosis factor alpha , lymphokine activated killer cell , cytotoxicity , cell , relb , immune system , immunology , interleukin 21 , in vitro , t cell , biology , nfkb1 , transcription factor , biochemistry , gene
Recently we reported that NK cells express GITR while tumor cells express GITR ligand (GITRL), and GITR‐GITRL interaction downregulates NK cell anti‐tumor immunity. Here we report that human tumor cells spontaneously release a soluble form of GITRL (sGITRL), which concentration‐dependently reduces NK cell cytotoxicity and IFN‐γ production in cocultures with tumor cells. While sGITRL does not induce apoptosis in NK cells, it diminishes nuclear localized RelB indicating that sGITRL negatively modulates NK cell NF‐κB activity. Furthermore, sGITRL was detected in 40 out of 50 sera of patients with various cancers, while no sGITRL was detectable in healthy volunteers. Addition of sGITRL containing patient sera to cocultures of NK cells and tumor cells significantly reduced NK cell cytotoxicity and IFN‐γ production. These inhibitory effects of sGITRL on NK cell effector functions could be restored by neutralization of sGITRL with a GITR‐Fc fusion protein. The strong correlation of tumor incidence and elevated sGITRL levels clearly suggests that sGITRL is released at significant amounts from malignant cells in vivo and may reduce immune surveillance of human tumors. Our data indicate that determination of sGITRL levels may be implemented as an immunological diagnostic marker in tumor patients, and GITRL‐neutralization may be employed in therapeutic strategies like adoptive NK cell transfer.