Understanding, and exploiting, the contribution of the immune system to the therapeutic efficacy of oncolytic virotherapy with vesicular stomatitis virus (VSV)

The activation of innate immune effector mechanisms against oncolytic viruses may contribute significantly to the clearance of both infected and uninfected tumor cells in an immuno-competent host. We show here, for the first time to our knowledge that the anti-tumor therapy of oncolytic VSV in the B16ova model depends upon signaling through MyD88 in host cells. In addition, we developed an in vitro tumor cell/bone marrow co-culture assay to dissect the innate immune sensor and effector responses to intra-tumoral VSV. Our data show that the Type III interferon, IL-28, is induced by viral activation of innate immune sensing cells and acts as a key mediator of VSV-mediated virotherapy of B16ova tumors. However, the anti-tumor activity of the oncolytic virus VSV against B16ova tumors in C57Bl/6 mice is predominantly due to anti-viral innate immune effectors rather than viral replication or adaptive T cell immunity. Using VSV encoding specific tumor associated antigens (TAA) to enhance the immunogenicity of the antigen, we show that antigen-expressing VSV effectively activated adoptively transferred, naive T cells with specificity for either a model foreign TAA (ova) or for an endogenous self TAA (gp100) in vivo and led to long term cures of mice bearing both local (virus injected) and distant tumors. Therefore, we describe here the role of both the innate and adaptive immune responses in mediating VSV virotherapy. Firstly, innate immune signaling through the MyD88 adaptor protein, and subsequent production of type I IFN and IL-28, is critical to the anti-tumor therapy of oncolytic VSV in the B16ova immune competent model.;Secondly, we show here that adoptive transfer of antigen specific cells can be successfully combined with intra-tumoral antigen expressing oncolytic virus to treat both the locally injected tumor and also systemic tumors not injected with virus.