Activation and Subversion of MDA5-Dependent Immune Responses by the Engineered Oncolytic Poliovirus PVSRIPO

Abstract

Cancer-specific cytopathogenicity of oncolytic viruses is often defined by viralsensitivity to innate antiviral immune responses, e.g. type I Interferons (IFNs), limitingcytotoxicity to cells lacking these responses. However, recent work suggests some cancercells inhibit IFN-sensitive oncolytic viruses, preventing efficacy. IFNs are also antiproliferative in cancer and activate anti-tumor immunity.In this work I show that the recombinant poliovirus PVSRIPO, currently inclinical trial as a treatment for glioblastoma, induces and evades IFN-β signaling incancer cell lines infected at low doses. Likewise, IFN-α treatment of cancer cellsinhibited PVSRIPO less than on the related encephalomyocarditis virus (EMCV).Antibody blockade of the IFN-α/β receptor had no effect on either virus in IFN-secretingmelanoma cell lines. Depletion of the pattern recognition receptor MDA5 or inhibition ofTBK1/IKKε eliminated IFN responses to PVSRIPO or EMCV and promoted EMCV, butnot PVSRIPO, replication. The Toll-like receptor 3 (TLR3) agonist poly(I:C) suppressedEMCV (semi-independently of type I IFN signaling) but not PVSRIPO. Thus, MDA5 andTLR3 provoke type I IFN-dependent and -independent antiviral effects, likely involvingupregulation of genes downstream of TBK1/IKKε. PVSRIPO subverts anti-viralimmunity in cancer cells at low doses and activates type I IFNs through MDA5,supporting its oncolytic and immunotherapeutic use even in IFN-competent cancers.