Interferon signaling mediates the cellular anti-viral response. Interferons act by inducing the expression of a broad repertoire of genes named "interferon-stimulated genes" (ISGs) and these are the "executers" of the anti-viral state. Interferons also induce growth arrest in different tumor cell types as certain ISGs also function as tumor-suppressors. Impairment of the interferon response is a characteristic of many tumors, which allows their hyper-proliferation but exposes the cancer cells to viral infection. We hypothesize that the silencing of ISGs that function as tumor-suppressors, through molecular mechanisms such as epigenetic regulation, defines subsets (in view of the large heterogeneity of cancerous cells) of tumors that can be optimally targeted by oncolytic virotherapy.
We have developed a novel virus with oncolytic potential, based on the Epizootic Hemorrhagic Disease virus (an orbivirus that naturally infects ruminants), and named it EHDV-TAU. Interferon-insensitive prostate cancer cells (LNCaP) were highly sensitive to EHDV-TAU infection. IFN-sensitive prostate cells (DU145) or primary human foreskin fibroblasts were resistant to EHDV-mediated killing. Abrogation of epigenetic silencing with 5-aza 2` deoxycytidine (5-AZA) and trichostatin A (TSA) rendered LNCaP cells resistant to EHDV-TAU Infection. Bioinformatics analyses of differentially expressed genes following 5-AZA/TSA treatments identified limited number of ISGs as potential inhibitors of EHDV-infection.
Our results correlate the potential of EHDV-TAU as an oncolytic virus with specific oncogenic cellular contexts, and highlight the importance of matching tumor types and oncolytic therapy agents, in the framework of personalized treatment.
