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Inhibition of NK Reactivity Against Solid Tumors by Platelet-Derived RANKL

1
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tuebingen 72076, Germany
2
Department of Hematology and Oncology, Eberhard Karls University, Tuebingen 72076, Germany
3
Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(3), 277; https://doi.org/10.3390/cancers11030277
Received: 29 January 2019 / Revised: 20 February 2019 / Accepted: 21 February 2019 / Published: 26 February 2019
(This article belongs to the Special Issue The Role of Thrombosis and Haemostasis in Cancer)
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Abstract

NK cells play an important role in tumor immunosurveillance. Their reactivity is governed by various activating and inhibitory surface receptors, which include several members of the TNF/TNF receptor family. For more than 50 years, it has been recognized that tumor immunosurveillance and in particular NK cell antitumor reactivity is largely influenced by platelets, but the underlying mechanisms remain to be fully elucidated. Here we report that upon activation, which reportedly occurs following interaction with cancer cells, platelets upregulate the TNF family member RANKL. Comparative analysis of the expression of RANK among different NK cell subsets and RANKL on platelets in cancer patients and healthy volunteers revealed a distinct malignant phenotype, and platelet-derived RANKL was found to inhibit the activity of normal NK cells against cancer cells. Notably, NK cell antitumor reactivity could be partially restored by application of denosumab, a RANKL-neutralizing antibody approved for treatment of benign and malignant osteolysis. Together, our data not only unravel a novel mechanism of tumor immune evasion mediated by platelets, but they also provide a functional explanation for the clinical observation that denosumab, beyond protecting from bone loss, may prolong disease-free survival in patients with solid tumors. View Full-Text
Keywords: NK cells; platelets; cancer; immune evasion; metastasis; RANK/RANKL; denosumab NK cells; platelets; cancer; immune evasion; metastasis; RANK/RANKL; denosumab
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Clar, K.L.; Hinterleitner, C.; Schneider, P.; Salih, H.R.; Maurer, S. Inhibition of NK Reactivity Against Solid Tumors by Platelet-Derived RANKL. Cancers 2019, 11, 277.

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