Cutting both ways: the innate immune response to oncolytic virotherapy

Oncolytic viruses (OVs), above and beyond infecting and lysing malignant cells, interact with the immune system in complex ways that have important therapeutic significance. While investigation into these interactions is still in its early stages, important insights have been made over the past two decades that will help improve the clinical efficacy of OV-based management strategies in cancer care moving forward. The inherent immunosuppression that defines the tumor microenvironment can be modified by OV infection, and the subsequent recruitment and activation of innate immune cells, in particular, is central to this. Indeed, neutrophils, macrophages, natural killer cells, and dendritic cells, as well as other populations such as myeloid-derived suppressor cells, are key to the immune escape that allows tumors to survive, but their natural response to infection can be exploited by virotherapy. While stimulation of innate immune cells by OVs can initiate antitumor responses, related antiviral activity can limit virus spread and direct cytopathogenic effects. In this review, we highlight how each innate immune cell population influences this balance of antitumor and antiviral forces during virotherapy, some of the important molecular pathways that have been identified, and specific therapeutic targets that have emerged through this work. We discuss the importance of OV-based combination therapies in optimizing antiviral and antitumor innate immune responses stimulated by virotherapy toward tumor eradication, and how these processes vary depending on the tumor and OV in question. Rather than concentrating on a particular OV species in the review, we present the range of effects that have been documented across OV types to emphasize the context-specific nature of these interactions and how this is important in the design of future OV-based treatment approaches.