In recent years, reoviruses have been of major interest in
immunotherapy because of their oncolytic properties. Preclinical and clinical trials, in which reovirus was used for the treatment of
melanoma and
glioblastoma, have paved the way for future clinical use of reovirus. However, little is known about how
reovirus infection affects the tumor microenvironment and immune response towards infected
tumor cells. Studies have shown that reovirus can directly stimulate natural killer (NK) cells, but how reovirus affects cellular
ligands on
tumor cells, which are ultimately key to
tumor recognition and elimination by NK cells, has not been investigated. We tested how
reovirus infection affects the binding of the NK Group-2 member D (
NKG2D) receptor, which is a dominant mediator of NK cell anti-
tumor activity. Using models of human-derived
melanoma and
glioblastoma tumors, we demonstrated that NKG2D
ligands are downregulated in
tumor cells post-
reovirus-infection due to the impaired translation of these
ligands in reovirus-infected cells. Moreover, we showed that downregulation of NKG2D
ligands significantly impaired the binding of NKG2D to infected
tumor cells. We further demonstrated that reduced recognition of NKG2D
ligands significantly alters NK cell anti-
tumor cytotoxicity in human primary NK cells and in the NK cell line NK-92. Thus, this study provides novel insights into reovirus-host interactions and could lead to the development of novel reovirus-based
therapeutics that enhance the anti-
tumor immune response.