Oncolytic virus treatment differentially affects the CD56ᵈⁱᵐ and CD56ᵇʳⁱᵍʰᵗ NK cell subsets in vivo and regulates a spectrum of human NK cell activity

Natural killer (NK) cells protect against intracellular infection and cancer. These properties are exploited in oncolytic virus (OV) therapy, where antiviral responses enhance anti-tumour immunity. We have analysed the mechanism by which reovirus, an oncolytic dsRNA virus, modulates human NK cell activity. Reovirus activates NK cells in a type I interferon (IFN-I) dependent manner, inducing STAT1 and STAT4 signalling in both CD56ᵈⁱᵐ and CD56ᵇʳⁱᵍʰᵗ NK cell subsets. Gene expression profiling revealed the dominance of IFN-I responses and identified induction of genes associated with NK cell cytotoxicity and cell cycle progression, with distinct responses in the CD56ᵈⁱᵐ and CD56ᵇʳⁱᵍʰᵗ subsets. However, reovirus treatment inhibited IL-15 induced NK cell proliferation in an IFN-I dependent manner and was associated with reduced AKT signalling. In vivo, human CD56ᵈⁱᵐ and CD56ᵇʳⁱᵍʰᵗ NK cells responded with similar kinetics to reovirus treatment, but CD56ᵇʳⁱᵍʰᵗ NK cells were transiently lost from the peripheral circulation at the peak of the IFN-I response, suggestive of their redistribution to secondary lymphoid tissue. Coupled with the direct, OV-mediated killing of tumour cells, the activation of both CD56ᵈⁱᵐ and CD56ᵇʳⁱᵍʰᵗ NK cells by antiviral pathways induces a spectrum of activity that includes the NK cell-mediated killing of tumour cells and modulation of adaptive responses via the trafficking of IFN-γ expressing CD56ᵇʳⁱᵍʰᵗ NK cells to lymph nodes.