Targeting IRF3 to increase the efficacy of oncolytic herpesvirus in mouse cancer cells

---

Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B962
Abstract ID: 6318

Presenting Author:
Fabian Benencia , Associate Professor of Immunology at Univ. of Ohio Heritage Col. of Osteopathic Med.

Abstract:

Oncolytic viruses (OV) specifically infect and kill tumor cells because these cells harbor a defective IFN response or express proteins that block apoptosis pathways. Oncolytic herpesvirus (HSV) infection activates pathogen recognition receptors as part of the innate immune response. HSV genome contains un-methylated CpG motifs which activate toll-like receptor TLR9, and during infection it generates dsRNA intermediates which can activate TLR3, RIG-I, MDA5, and STING. Signaling pathways downstream of dsRNA recognition activate pro-apoptotic IRF3 leading to the production of type-I IFN, induction of co-stimulatory molecules and caspase cascade activation. We hypothesize that inhibiting IRF3 will diminish the antiviral response, increasing the efficacy of the OV. Here, we  inhibited IRF3 expression in murine ovarian cancer cells with phenylmethimazole (C10), which inhibits dsRNA-triggered IRF3 signaling, preventing induction of type-I IFN gene expression, and type-I IFN production and signaling. Cancer cells treated with C10 were more susceptible to oncolytic HSV, as measured by increased cell death. The innate antiviral response in those cells was diminished as shown by lower levels of CXCL10 produced by infected cells. The levels of immunogenic cell death markers, e.g., HGMB1, were not decreased in C10-treated infected cells, indicating that the immunogenicity of the killed tumor cells is preserved. Thus, targeting IRF3 can be a strategy to increase the efficacy of OV.