Glucocorticoid-induced TNFR-related protein (GITR) ligand modulates cytokine release and NK cell reactivity in chronic lymphocytic leukemia (CLL)

Abstract

Natural killer (NK) cells play an important role in the immunosurveillance of hematopoietic malignancies. Their reactivity is influenced by activating and inhibitory signals mediated by tumor-expressed ligands for NK receptors. Many members of the tumor necrosis factor (TNF) family modulate differentiation, proliferation, activation and death of both tumor and immune effector cells. The TNF receptor family member glucocorticoid-induced TNFR-related protein (GITR) stimulates anti-tumor immunity in mice, but available data indicate that GITR may mediate different effects in mice and men and impairs the reactivity of human NK cells. Here, we comprehensively studied the expression and function of GITR ligand (GITRL) in leukemia. Among the different leukemia entities, pronounced expression of GITRL on leukemic cells was observed in chronic lymphocytic leukemia (CLL), and the GITR receptor was expressed at significantly higher levels on NK cells of CLL patients compared with healthy controls. Upon GITR --GITRL interaction, signaling via GITRL into the leukemia cells induced the release of interleukin (IL)-6, IL-8 and TNF, which act as growth and survival factors for CLL cells. In addition, GITRL impaired both direct and Rituximab-induced degranulation, cytotoxicity and interferon-g production of NK cells, which could be restored by GITR blocking antibodies. Thus, GITRL may contribute to disease pathophysiology and resistance to direct and Rituximab-induced NK reactivity in CLL.

GITR Ligand Provided by Thrombopoietic Cells Inhibits NK Cell Antitumor Activity

“…We and others have previously reported that GITR is expressed on NK cells and reduces their cytotoxicity and IFN-g production upon engagement of GITRL (20,24,36,38,39). In this study, we demonstrate that tumor cells rapidly get coated in the presence of platelets, resulting in impaired NK antitumor reactivity, which is in line with findings of previous studies (6,7,11).…”

“…Thus, interfering with GITR in mouse models may cause various effects that influence multiple cell types that interact via GITR-GITRL. Perhaps most importantly, results by us and others revealed that the consequences of GITR triggering may differ in human and mouse NK cells (20,24,35,36,38,39). Our in vitro study in turn enabled the detailed dissection of the mechanisms by which GITR and its platelet-expressed ligand may contribute to the evasion of tumor cells from NKmediated immune surveillance.…”

“…To establish the functional significance of platelet-derived GITRL pseudoexpression on tumor cells, and because GITR inhibits the reactivity of human NK cells (20,24,36,38,39), SK-Mel, PC3, and SK-BR-3 tumor cells were coincubated with NK cells with and without antecedent coating by platelets. Intentionally, platelets and NK cells were from different donors to exclude potential inhibitory effects by autologous MHC class I, which is also highly expressed on platelets (40).…”

Receptor Activator for NF-κB Ligand in Acute Myeloid Leukemia: Expression, Function, and Modulation of NK Cell Immunosurveillance

“…Although the latter may be due to contamination with RANKL-expressing healthy cells, the lack of correlation between mRNA expression and prevalence of the respective soluble and membrane-bound protein points to a potential regulatory or mutational blockade of RANKL expression by posttranscriptional and/or posttranslational mechanisms in the individual patients. This again is in line with findings on the expression and release of other TNF family members in leukemic cells (13,14,40,41).…”

“…Numerous TNF/TNFR family members are expressed by NK cells and are upregulated in malignant disease, where they influence NK reactivity upon interaction with their target cell-expressed coun- terparts (13,14,(39)(40)(41). As available data indicated that RANK can be expressed by NK cells (26), we comparatively analyzed RANK expression on NK cells of healthy donors and our AML patients.…”