Engineering oncolytic measles virus to circumvent the intracellular innate immune response.
The innate antiviral responses of tumor cells are often impaired but may still be sufficient to impede the intratumoral spread of an oncolytic virus. Here, we establish that the oncolytic measles virus (MV-eGFP) induces interferon (IFN) production in human myeloma and ovarian cancer cells. In addition, MV gene expression and virus progeny production were inhibited by IFN treatment of these tumor cells. The P gene of wild-type measles virus encodes P/V/C proteins known to antagonize IFN induction and/or response. We therefore engineered MV-eGFP for IFN evasion and more efficient intratumoral spread by arming it with the P gene from wild-type IC-B strain MV, thus generating MV-eGFP-Pwt. The chimeric virus exhibited reduced IFN sensitivity and diminished capacity to induce IFN in BJAB lymphoma, ARH-77 myeloma cells, and activated peripheral blood mononuclear cells. Interestingly, unlike the wild-type MV, MV-eGFP-Pwt was unable to shut down IFN induction completely. In immunocompromised mice bearing human myeloma xenografts, intravenously administered MV-eGFP-Pwt showed significantly enhanced oncolytic potency compared to MV-eGFP. These results indicate that oncolytic viruses are subject to control by the innate immune defenses of human tumor cells and may therefore be more effective if their natural ability to combat innate immunity is maintained.
Haralambieva
Iana
I
1Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Iankov
Ianko
I
Hasegawa
Kosei
K
Harvey
Mary
M
Russell
Stephen J
SJ
Peng
Kah-Whye
KW
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D017930:Genes, Reporter / Q000235:genetics; D005818:Genetic Engineering; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007275:Injections, Intravenous; D007372:Interferons / Q000096:biosynthesis; D008459:Measles virus / Q000235:genetics*; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D050504:Oncolytic Viruses / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D010750:Phosphoproteins; C069181:V protein, measles virus; D014764:Viral Proteins; D007372:Interferons