Constitutive impaired expression of antiviral effectors sensitizes melanoma cells viral oncolysis

Immunoediting of malignant cells commonly dampens the function of interferon antiviral responses and the expression of interferon-stimulated genes, making cancer cells potentially susceptible to viral attacks. Oncolytic virotherapy exploits such characteristics to specifically infect and kill cancer cells and stimulate anti-tumor immunity. Our labs have developed a novel oncolytic virus, the Epizootic Hemorrhagic Disease Virus-Tel Aviv University (EHDV-TAU). Starting from the Ibaraki strain of EHDV2, and employing an in vitro evolution process in interferon-defective LNCaP cells, we have selected EHDV-TAU. Initial characterization of EHDV-TAU showed a million-fold increased replication efficiency in LNCaP cells, selectivity towards cancer cells, and the ability to induce different forms of cell death. In this study, we probe for the efficiency and safety of EHDV-TAU with the B16F10 murine melanoma in immunocompetent C57BL6 mice.

B16F10 melanoma cells are susceptible to EHDV-TAU infection and oncolysis with high cell death rate and an increase in the formation of infectious particles. This increased susceptibility correlated with near-absent constitutive expression of viral sensors and interferon-stimulated genes and with the inability to mount JAK/STAT-based antiviral responses upon exposure to EHDV-TAU. Analysis with inhibitors of DNA methylation and histone deacetylation suggest the role of epigenetic silencing of antiviral genes in B16F10 cells. Notably, infected cells retained the ability to secrete immuno-attractants, suggesting their ability to activate immune cells. Indeed, in vivo, EHDV-TAU markedly reduced tumor volume, enhanced survival and promoted intratumoral infiltration of effector immune cells. Overall, our results suggest that EHDV-TAU may function as a novel and effective anti-tumor agent.