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-γ 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.