{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T02:11:15Z","timestamp":1773022275365,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,2,26]],"date-time":"2019-02-26T00:00:00Z","timestamp":1551139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institutional Strategy of the University of Tuebingen (Deutsche Forschungsgemeinschaft)","award":["ZUK 63"],"award-info":[{"award-number":["ZUK 63"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SA1360\/7-3"],"award-info":[{"award-number":["SA1360\/7-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["2007.115.3"],"award-info":[{"award-number":["2007.115.3"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["111828"],"award-info":[{"award-number":["111828"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["111134"],"award-info":[{"award-number":["111134"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["31003A-176256"],"award-info":[{"award-number":["31003A-176256"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers11030277","type":"journal-article","created":{"date-parts":[[2019,2,26]],"date-time":"2019-02-26T11:00:44Z","timestamp":1551178844000},"page":"277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Inhibition of NK Reactivity Against Solid Tumors by Platelet-Derived RANKL"],"prefix":"10.3390","volume":"11","author":[{"given":"Kim L.","family":"Clar","sequence":"first","affiliation":[{"name":"Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tuebingen 72076, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clemens","family":"Hinterleitner","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Eberhard Karls University, Tuebingen 72076, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0677-9409","authenticated-orcid":false,"given":"Pascal","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helmut R.","family":"Salih","sequence":"additional","affiliation":[{"name":"Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tuebingen 72076, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Maurer","sequence":"additional","affiliation":[{"name":"Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tuebingen 72076, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1073\/pnas.61.1.46","article-title":"Antimetastatic effects associated with platelet reduction","volume":"61","author":"Gasic","year":"1968","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nrc3004","article-title":"Contribution of platelets to tumour metastasis","volume":"11","author":"Gay","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.ccr.2011.09.009","article-title":"Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis","volume":"20","author":"Labelle","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1159\/000323936","article-title":"Modulation of Natural Killer Cell Anti-Tumor Reactivity by Platelets","volume":"4","author":"Placke","year":"2011","journal-title":"J. Innate Immun."},{"key":"ref_5","first-page":"1295","article-title":"Lysis of tumor cells by natural killer cells in mice is impeded by platelets","volume":"59","author":"Nieswandt","year":"1999","journal-title":"Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ccell.2017.06.009","article-title":"Control of Metastasis by NK Cells","volume":"32","author":"Gonzalez","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1146\/annurev.immunol.23.021704.115526","article-title":"NK cell recognition","volume":"23","author":"Lanier","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/S0092-8674(01)00237-9","article-title":"The TNF and TNF receptor superfamilies: Integrating mammalian biology","volume":"104","author":"Locksley","year":"2001","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1038\/leu.2015.50","article-title":"Neutralization of (NK-cell-derived) B-cell activating factor by Belimumab restores sensitivity of chronic lymphoid leukemia cells to direct and Rituximab-induced NK lysis","volume":"29","author":"Wild","year":"2015","journal-title":"Leukemia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1158\/2326-6066.CIR-17-0212","article-title":"The Immune Checkpoint Modulator OX40 and Its Ligand OX40L in NK-Cell Immunosurveillance and Acute Myeloid Leukemia","volume":"6","author":"Nuebling","year":"2018","journal-title":"Cancer Immunol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8202","DOI":"10.1074\/jbc.M708944200","article-title":"Glucocorticoid-induced tumor necrosis factor receptor negatively regulates activation of human primary natural killer (NK) cells by blocking proliferative signals and increasing NK cell apoptosis","volume":"283","author":"Liu","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7775","DOI":"10.1158\/0008-5472.CAN-09-2123","article-title":"Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity","volume":"69","author":"Kopp","year":"2009","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e1364827","DOI":"10.1080\/2162402X.2017.1364827","article-title":"Platelet-mediated shedding of NKG2D ligands impairs NK cell immune-surveillance of tumor cells","volume":"7","author":"Maurer","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1111\/j.1600-065X.2006.00460.x","article-title":"Activation and self-tolerance of natural killer cells","volume":"214","author":"Gasser","year":"2006","journal-title":"Immunol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-11-1872","article-title":"Platelet-derived MHC Class I confers a pseudo- normal phenotype to cancer cells that subverts the anti-tumor reactivity of natural killer immune cells","volume":"72","author":"Placke","year":"2011","journal-title":"Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"154","DOI":"10.4049\/jimmunol.1103194","article-title":"GITR ligand provided by thrombopoietic cells inhibits NK cell antitumor activity","volume":"189","author":"Placke","year":"2012","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"425","DOI":"10.3109\/09537104.2014.920081","article-title":"Platelet-derived RANK ligand enhances CCL17 secretion from dendritic cells mediated by thymic stromal lymphopoietin","volume":"26","author":"Nakanishi","year":"2015","journal-title":"Platelets"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Schmiedel, B.J., Grosse-Hovest, L., and Salih, H.R. (2013). A \u201cvicious cycle\u201d of NK-cell immune evasion in acute myeloid leukemia mediated by RANKL?. Oncoimmunology, 2.","DOI":"10.4161\/onci.23850"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"821","DOI":"10.4049\/jimmunol.1201792","article-title":"Receptor Activator for NF-kappaB Ligand in Acute Myeloid Leukemia: Expression, Function, and Modulation of NK Cell Immunosurveillance","volume":"190","author":"Schmiedel","year":"2013","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3378","DOI":"10.1182\/blood.V85.12.3378.bloodjournal85123378","article-title":"Tumor necrosis factor ligand superfamily: Involvement in the pathology of malignant lymphomas","volume":"85","author":"Gruss","year":"1995","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3341","DOI":"10.1182\/blood-2015-12-629055","article-title":"Exploitation of natural killer cells for the treatment of acute leukemia","volume":"127","author":"Handgretinger","year":"2016","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3716","DOI":"10.4049\/jimmunol.173.6.3716","article-title":"Cross-talk between activated human NK cells and CD4+ T cells via OX40-OX40 ligand interactions","volume":"173","author":"Zingoni","year":"2004","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s00262-015-1761-x","article-title":"NK-92: An \u2018off-the-shelf therapeutic\u2019 for adoptive natural killer cell-based cancer immunotherapy","volume":"65","author":"Suck","year":"2016","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1056\/NEJMoa0809493","article-title":"Denosumab for prevention of fractures in postmenopausal women with osteoporosis","volume":"361","author":"Cummings","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1056\/NEJMoa0809003","article-title":"Denosumab in men receiving androgen-deprivation therapy for prostate cancer","volume":"361","author":"Smith","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1002\/1097-0142(20010801)92:3<460::AID-CNCR1344>3.0.CO;2-D","article-title":"Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: Potential implications for the pathogenesis and treatment of malignant bone diseases","volume":"92","author":"Hofbauer","year":"2001","journal-title":"Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.ctrv.2007.09.002","article-title":"RANK ligand as a therapeutic target for bone metastases and multiple myeloma","volume":"34","author":"Roodman","year":"2008","journal-title":"Cancer Treat. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gnant, M., Pfeiler, G., Dubsky, P.C., Hubalek, M., Greil, R., Jakesz, R., Wette, V., Balic, M., Haslbauer, F., and Melbinger-Zeinitzer, E. (2016). The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. Cancer Res.","DOI":"10.1200\/jco.2015.33.15_suppl.504"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/nature09707","article-title":"Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling","volume":"470","author":"Tan","year":"2011","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1158\/0008-5472.CAN-08-2650","article-title":"Glucocorticoid-induced tumor necrosis factor receptor-related protein ligand subverts immunosurveillance of acute myeloid leukemia in humans","volume":"69","author":"Baessler","year":"2009","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3058","DOI":"10.1182\/blood-2009-06-227934","article-title":"CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells","volume":"115","author":"Baessler","year":"2010","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/35393","article-title":"CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells","volume":"391","author":"Henn","year":"1998","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1189\/jlb.69.1.123","article-title":"Activated human platelets express Fas-L and induce apoptosis in Fas-positive tumor cells","volume":"69","author":"Ahmad","year":"2001","journal-title":"J. Leukoc. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.exphem.2004.07.022","article-title":"Expression of TNF-related apoptosis-inducing ligand (TRAIL) in megakaryocytes and platelets","volume":"32","author":"Crist","year":"2004","journal-title":"Exp. Hematol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Plantureux, L., Mege, D., Crescence, L., Dignat-George, F., Dubois, C., and Panicot-Dubois, L. (2018). Impacts of Cancer on Platelet Production, Activation and Education and Mechanisms of Cancer-Associated Thrombosis. Cancers, 10.","DOI":"10.3390\/cancers10110441"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"36083","DOI":"10.1074\/jbc.M113.506220","article-title":"CD154 is released from T-cells by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and ADAM17 in a CD40 protein-dependent manner","volume":"288","author":"Yacoub","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1016\/j.ajpath.2011.02.003","article-title":"RANKL expression specifically observed in vivo promotes epithelial mesenchymal transition and tumor progression","volume":"178","author":"Yamada","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/B978-0-12-801430-1.00005-6","article-title":"Tools and techniques to study ligand-receptor interactions and receptor activation by TNF superfamily members","volume":"545","author":"Schneider","year":"2014","journal-title":"Methods Enzymol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"657","DOI":"10.4049\/jimmunol.0904117","article-title":"Cutting edge: NKp80 uses an atypical hemi-ITAM to trigger NK cytotoxicity","volume":"186","author":"Dennehy","year":"2011","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1089\/10430349950018030","article-title":"Characterization of genetically altered, interleukin 2-independent natural killer cell lines suitable for adoptive cellular immunotherapy","volume":"10","author":"Tam","year":"1999","journal-title":"Hum. Gene Ther."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Koerner, S.P., Andre, M.C., Leibold, J.S., Kousis, P.C., Kubler, A., Pal, M., Haen, S.P., Buhring, H.J., Grosse-Hovest, L., and Jung, G. (2016). An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia. Leukemia.","DOI":"10.1038\/leu.2016.194"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/3\/277\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:34:52Z","timestamp":1760186092000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/3\/277"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,26]]},"references-count":41,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["cancers11030277"],"URL":"https:\/\/doi.org\/10.3390\/cancers11030277","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,26]]}}}