title: Glucocorticoid-induced tumor necrosis factor receptor-related protein ligand subverts immunosurveillance of acute myeloid leukemia in humans.
abstract: The reciprocal interaction of tumor cells with the immune system is influenced by various members of the tumor necrosis factor (TNF)/TNF receptor (TNFR) family, and recently, glucocorticoid-induced TNFR-related protein (GITR) was shown to stimulate antitumor immunity in mice. However, GITR may mediate different effects in mice and men and impairs the reactivity of human natural killer (NK) cells. Here, we studied the role of GITR and its ligand (GITRL) in human acute myeloid leukemia (AML). Surface expression of GITRL was observed on AML cells in six of seven investigated cell lines, and 34 of 60 investigated AML patients whereas healthy CD34(+) cells did not express GITRL. Furthermore, soluble GITRL (sGITRL) was detectable in AML patient sera in 18 of 55 investigated cases. While the presence of GITRL was not restricted to a specific AML subtype, surface expression was significantly associated with monocytic differentiation. Signaling via GITRL into patient AML cells induced the release of TNF and interleukin-10 (IL-10), and this was blocked by the inhibition of mitogen-activated protein kinases extracellular signal-regulated kinase 1/2. Furthermore, triggering GITR by surface-expressed and sGITRL impaired NK cell cytotoxicity and IFN-gamma production in cocultures with leukemia cells, and NK cell reactivity could be restored by blocking GITR and neutralization of sGITRL and IL-10. Thus, whereas a stimulatory role of the GITR-GITRL system in mouse antitumor immunity has been reported, our data show that in humans GITRL expression subverts NK cell immunosurveillance of AML. Our results provide useful information for therapeutic approaches in AML, which, like haploidentical stem cell transplantation, rely on a sufficient NK cell response.
authors.affiliation: Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Baessler
authors.forename: Matthias
authors.initials: M
authors.lastname: Krusch
authors.forename: Benjamin Joachim
authors.initials: BJ
authors.lastname: Schmiedel
authors.forename: Mercedes
authors.initials: M
authors.lastname: Kloss
authors.forename: Katrin Miriam
authors.initials: KM
authors.lastname: Baltz
authors.forename: Alexander
authors.initials: A
authors.lastname: Wacker
authors.forename: Helga Maria
authors.initials: HM
authors.lastname: Schmetzer
authors.forename: Helmut Rainer
authors.initials: HR
authors.lastname: Salih
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007157:Immunologic Surveillance / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D007951:Leukemia, Myeloid / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000096:biosynthesis / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines; C478967:TNFSF18 protein, human; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma