Antiviral humoral immunity: Enemy or ally of viral immunotherapy?

Oncolytic viruses are gaining traction as novel cancer immunotherapy tools given their ability to selectively target transformed cells. While direct tumor debulking was historically considered their primary mode of action, it is now appreciated that antitumor immunity significantly contributes to therapeutic efficacy. While T cells play a key role, less is known about humoral immunity in oncolytic virotherapy. While systemic delivery is the clinically preferred route for therapy administration, most oncolytic viruses are delivered directly to the tumor to avoid neutralization by pre-existing or therapy-induced immunity. In this review, we discuss emerging data showing the contribution of antiviral immunity to oncolytic activity along with growing evidence that questions dogma surrounding inhibitory activity of neutralizing antibodies. We further discuss how route of administration, tumor vascularization, host and cellular range, and oncolytic virus mechanism of action influence the role of the humoral immune response to therapy outcomes. We end the discussion with additional factors to consider, such as regulatory B cells, immunoglobulin isotype, Fc-mediated functions and the importance of choosing the right pre-clinical model that may contribute to overall therapy outcomes that are not routinely considered in pre-clinical and clinical studies of viral immunotherapies.