Activation and Subversion of MDA5-Dependent Immune Responses by the Engineered Oncolytic Poliovirus PVSRIPO
Cancer-specific cytopathogenicity of oncolytic viruses is often defined by viral
sensitivity to innate antiviral immune responses, e.g. type I Interferons (IFNs), limiting
cytotoxicity to cells lacking these responses. However, recent work suggests some cancer
cells 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 in
clinical trial as a treatment for glioblastoma, induces and evades IFN-β signaling in
cancer cell lines infected at low doses. Likewise, IFN-α treatment of cancer cells
inhibited 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-secreting
melanoma cell lines. Depletion of the pattern recognition receptor MDA5 or inhibition of
TBK1/IKKε eliminated IFN responses to PVSRIPO or EMCV and promoted EMCV, but
not PVSRIPO, replication. The Toll-like receptor 3 (TLR3) agonist poly(I:C) suppressed
EMCV (semi-independently of type I IFN signaling) but not PVSRIPO. Thus, MDA5 and
TLR3 provoke type I IFN-dependent and -independent antiviral effects, likely involving
upregulation of genes downstream of TBK1/IKKε. PVSRIPO subverts anti-viral
immunity in cancer cells at low doses and activates type I IFNs through MDA5,
supporting its oncolytic and immunotherapeutic use even in IFN-competent cancers.
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