Exploiting an Achilles’ Heel of Cancer with a Novel Oncolytic Virus

Selective pressure applied by immune surveillance mechanisms may modify expression or function of regulators of cell autonomous immunity in cancer cells. Such modified expression alters interactions between cancer cells and the immune component of the tumor microenvironment, and weakens antiviral responses of cancer cells. However, the prevalence of such modifications, their molecular underpinnings, the degree of coordination in altered expression of different genes, and their effect on susceptibility of tumors to viral oncolysis, are uncharacterized. In this study, we analyzed gene expression and promoter methylation employing The Cancer Genome Atlas skin melanoma database, and identified and coordinated alterations in expression of STAT1-related genes, including regulators and effectors of antiviral responses. To probe if such changes affect the susceptibility of melanoma cells to viral oncolysis, we employed B16F10 murine melanoma as tumor model, immortalized mouse skin fibroblasts as control, and the oncolytic Epizootic Hemorrhagic Disease Virus-Tel Aviv University (EHDV-TAU). B16F10 cells were responsive to interferon stimuli but failed to elicit interferon responses upon challenge with EHDV-TAU, resulting in productive viral infection and oncolysis. Antiviral signaling in B16F10 was restored via pre-incubation with interferon, which elevated expression of RNA viral sensors. In mice, intra-tumoral injection of EHDV-TAU reduced tumor growth in treated and distal tumors and enhanced infiltration of effector immune cells; both in accord with its ability to induce tumor cell oncolysis and stimulation of anti-tumor immunity.