Immunodominant Antiviral T Cell Responses Outcompete Antitumor T Cell Responses to Reduce the Efficacy of Oncolytic Viroimmunotherapy.

The paradigm in the field of oncolytic virotherapy proposes that tumor cell killing by an oncolytic virus (OV) culminates in the priming of antitumor CD8+ T cells. However, this ignores the impact a highly immunodominant antiviral response against the OV has on the subdominant antitumor response, particularly regarding the naturally low affinity of tumor antigens to their cognate T cell receptors. To investigate this experimentally, we first studied the interaction between the two responses in B16 and MC38 tumor models both expressing ovalbumin (OVA). Contrary to the accepted paradigm, the inflammatory vesicular stomatitis virus (VSV) failed to expand OVA-specific T cells in vivo unless armed with tumor-associated antigen (TAA). In fact, treatment with the control VSV led to the ablation of antitumor T cells and a shift toward dysfunction as determined by the upregulation of markers including LAG3 and CD39 correlating with lower rates of survival. Combination with anti-PD-1 immune checkpoint blockade therapy significantly improved survival only when VSV expressed TAA. VSV expressing altered peptide ligand (APL) variants of tumor antigens, which evade mechanisms of central tolerance expanded near-self antigen specific T cells with the ability to cross react with tolerized tumor antigens, thus providing an antitumor effector population capable of proliferating in the presence of a potent antiviral response. Taken together, these findings offer a rational approach to OV design which preserves acute antitumor therapy provided by antiviral innate and T cell responses whilst promoting the induction of tumor-specific T cells.