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.IMPORTANCE Reovirus infects much of the population during childhood, causing mild disease, and hence is considered to be efficiently controlled by the immune system. Reovirus also specifically infects
tumor cells, leading to
tumor death, and is currently being tested in human clinical trials for
cancer therapy. The mechanisms by which our immune system controls
reovirus infection and
tumor killing are not well understood. We report here that natural killer (NK) cells recognize a
viral protein named sigma1 through the NK cell-activating
receptor NKp46. Using several mouse
tumor models, we demonstrate the importance of NK cells in protection from
reovirus infection and in reovirus killing of
tumors in vivo Collectively, we identify a new
ligand for the
NKp46 receptor and provide evidence for the importance of NKp46 in the control of
reovirus infections and in reovirus-based
cancer therapy.