Rizk, Soha S.

Abstract 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 with regard to 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 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 while promoting the induction of tumor-specific T cells. Significance: Oncolytic viruses can induce an antiviral T-cell response that occludes an antitumor response, challenging the paradigm in the field and elucidating strategies to optimize the efficacy of oncolytic viroimmunotherapy.

Abstract 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 antitumor response which has been weakened by mechanisms of central tolerance. Here, we show that inflammatory Vesicular Stomatitis Virus (VSV) failed to prime an adoptively transferred, or pre-existing, population of tumor-reactive T cells.Combination with αPD1 immune checkpoint blockade therapy improved survival only when VSV expressed tumor associated antigens (TAA). These data show that, in this model, the highly inflammatory OV VSV alone actively outcompetes antitumor immunity. However, we also show that viral expression of a mutant near-self TAA can break central tolerance expanding heteroclitic self-reactive and near-self-reactive T cells, thus overcoming viral immunodominance by promoting tumor-specific T cell proliferation in parallel with expanding antiviral T cells.