Induction of robust type I interferon levels by oncolytic reovirus requires both viral replication and IFNAR signaling.

Oncolytic viruses are promising agents for cancer therapy, because they selectively infect and kill tumor cells, and also because they trigger immune responses that can boost anti-cancer immunity. Key to the latter process is the production of type I interferons (IFN-Is) that can turn non-inflamed "cold" tumors into "hot" ones. Besides this desired anti-cancer effect, IFN-Is are antiviral and successful oncolytic virotherapy thus relies on tightly controlled IFN-I levels. This requires a profound understanding of when and how tumor cells induce IFN-I in response to specific viruses. In this study, we uncovered two key factors that augment IFN-I production in transformed human myeloid cells infected with a tumor-selective reovirus. Viral replication and interferon-α/β receptor (IFNAR) signaling progressively reinforced the levels of IFN-I expressed by infected cells. Mechanistically, both augmented the activation of IRF3, a key transcription factor for IFNβ expression. Our findings imply that reovirus-permissive tumor cells themselves are a major source of IFN-I expression. As tumors can perturb the IFNAR pathway for their own survival, reovirus exposed IFNAR-unresponsive tumors may need additional therapeutic intervention to promote the secretion of sufficient IFN-I into the tumor microenvironment. Our increased understanding of the parameters that affect reovirus-induced IFN-I levels could aid in the design of tailored virus-based cancer therapies.