The recent approval of oncolytic virus for therapy of melanoma patients has increased the need for precise evaluation of the mechanisms by which oncolytic viruses affect tumor growth. Here we show that the human NK cell-activating receptor NKp46 and the orthologous mouse protein NCR1 recognize the reovirus sigma1 protein in a sialic-acid-dependent manner. We identify sites of NKp46/NCR1 binding to sigma1 and show that sigma1 binding by NKp46/NCR1 leads to NK cell activation in vitro. Finally, we demonstrate that NCR1 activation is essential for reovirus-based therapy in vivo. Collectively, we have identified sigma1 as a novel ligand for NKp46/ NCR1 and demonstrated that NKp46/NCR1 is needed both for clearance of reovirus infection and for reovirus-based tumor therapy.
Bibliographical noteFunding Information:
This study was supported by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC (grant agreement number 320473-BacNK). Further support came from the Israel Science Foundation, the GIF Foundation, the Lewis Family Foundation, the ICRF professorship grant, the Helmholtz Israel grant, and the Rosetrees Trust (all to O.M.). Further support came from the I-CORE Program of the Planning and Budgeting Committee and the Israel Science Foundation and from the I-Core on Chromatin and RNA in Gene Regulation. O.M. is a Crown Professor of Molecular Immunology. The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript.
© 2017 American Society for Microbiology.