As well as inducing direct oncolysis, reovirus treatment of melanoma is associated with activation of innate and adaptive anti-tumour immune responses.

Here we characterise the effects of conditioned media from reovirus-infected, dying human melanoma cells (reoTCM), in the absence of live virus, to address the immune bystander potential of reovirus therapy. In addition to RANTES, IL-8, MIP-1alpha and MIP-1beta, reovirus-infected melanoma cells secreted eotaxin, IP-10 and the type 1 interferon IFN-beta. To address the mechanisms responsible for the inflammatory composition of reoTCM, we show that IL-8 and IFN-beta secretion by reovirus-infected melanoma cells was associated with activation of NF-kappaB and decreased by pre-treatment with small molecule inhibitors of NF-kappaB and PKR; specific siRNA-mediated knockdown further confirmed a role for PKR. This pro-inflammatory milieu induced a chemotactic response in isolated natural killer (NK) cells, dendritic cells (DC) and anti-melanoma cytotoxic T cells (CTL). Following culture in reoTCM, NK cells upregulated CD69 expression and acquired greater lytic potential against tumour targets. Furthermore, melanoma cell-loaded DC cultured in reoTCM were more effective at priming adaptive anti-tumour immunity.

These data demonstrate that the PKR- and NF-kappaB-dependent induction of pro-inflammatory molecules that accompanies reovirus-mediated killing can recruit and activate innate and adaptive effector cells, thus potentially altering the tumour microenvironment to support bystander immune-mediated therapy as well as direct viral oncolysis.

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