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Immunology

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

Leukemia volume 26, pages 991–1000 (2012)Cite this article

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-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.

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Acknowledgements

This study is supported by grants from the Wilhelm Sander Stiftung (2007.115.2) and the Deutsche Krebshilfe (108208 and 109620).

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  1. C Buechele and T Baessler: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Oncology, Eberhard Karls-University, Tuebingen, Germany

    C Buechele, T Baessler, S Wirths, J U Schmohl, B J Schmiedel & H R Salih

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  1. C Buechele
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Correspondence to H R Salih.

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Buechele, C., Baessler, T., Wirths, S. et al. Glucocorticoid-induced TNFR-related protein (GITR) ligand modulates cytokine release and NK cell reactivity in chronic lymphocytic leukemia (CLL). Leukemia 26, 991–1000 (2012). https://doi.org/10.1038/leu.2011.313

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