The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells

作     者：Paolino, Magdalena Choidas, Axel Wallner, Stephanie Pranjic, Blanka Uribesalgo, Iris Loeser, Stefanie Jamieson, Amanda M. Langdon, Wallace Y. Ikeda, Fumiyo Fededa, Juan Pablo Cronin, Shane J. Nitsch, Roberto Schultz-Fademrecht, Carsten Eickhoff, Jan Menninger, Sascha Unger, Anke Torka, Robert Gruber, Thomas Hinterleitner, Reinhard Baier, Gottfried Wolf, Dominik Ullrich, Axel Klebl, Bert M. Penninger, Josef M. 

作者机构：Austrian Acad Sci Inst Mol Biotechnol IMBA A-1030 Vienna Austria Lead Discovery Ctr GmbH D-44227 Dortmund Germany Med Univ Innsbruck A-6020 Innsbruck Austria Brown Univ Dept Microbiol & Immunol Providence RI 02912 USA Univ Western Australia Sch Pathol & Lab Med Perth WA 6009 Australia Max Planck Inst Biochem Dept Mol Biol D-82152 Martinsried Germany Univ Hosp Bonn D-53127 Bonn Germany 

出 版 物：《NATURE》 (自然)

年 卷 期：2014年第507卷第7493期

页      面：508-+页

核心收录：

学科分类：07[理学] 08[工学] 

基　　金：European Research Council (ERC) Era of Hope/DoD Innovator Award Institute of Molecular Biotechnology (IMBA) Austrian National Foundation Austrian Academy of Sciences GEN-AU (AustroMouse) EU ERC 

主　　题：Immunosurveillance 

摘      要：Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy(1). New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies(2). Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology(3). This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a pill that awakens the innate immune system to kill cancer metastases.