VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling

Mol Ther. 2011 Jan;19(1):150-8. doi: 10.1038/mt.2010.225. Epub 2010 Oct 19.


We show here, for the first time to our knowledge, that the antitumor therapy of oncolytic vesicular stomatitis virus (VSV) in the B16ova model depends upon signaling through myeloid differentiation primary response gene 88 (MyD88) in host cells. VSV-mediated therapy of B16ova tumors was abolished in MyD88(-/-) mice despite generation of antigen-specific T cell responses similar to those in immune-competent mice. Mice defective in only toll-like receptor 4 (TLR4), TLR7, or interleukin 1 (IL-1) signaling retained VSV-induced therapy, suggesting that multiple, redundant pathways of innate immune activation by the virus contribute to antitumor immune reactivity. Lack of MyD88 signaling was associated with decreased expression of proinflammatory cytokines and neutrophil infiltration in response to intratumoral virus, as well as decreased infiltration of draining lymph nodes (LN) with plasmacytoid dendritic cells (pDCs) (CD11b(-)GR1(+)B220(+)) and myeloid-derived suppressor cells (CD11b(+)GR1(+)F4/80(+)). MyD88 signaling in response to VSV was also closely associated with a type I interferon (IFN) response. This inhibited virus replication within the tumor but also protected the host from viral dissemination from the tumor. Therefore, the innate immune response to oncolytic viruses can be, simultaneously, protherapeutic, antioncolytic, and systemically protective. These paradoxically conflicting roles need to be carefully considered in future strategies designed to improve the efficacy of oncolytic virotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / immunology
  • Dendritic Cells / immunology
  • Immunity, Innate / immunology
  • Interferon Type I / immunology
  • Interferon Type I / metabolism
  • Interleukin-1 / deficiency
  • Interleukin-1 / genetics
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / therapy*
  • Melanoma, Experimental / virology
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • Oncolytic Virotherapy / methods*
  • Signal Transduction
  • T-Lymphocytes / immunology
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 7 / deficiency
  • Toll-Like Receptor 7 / genetics
  • Vesicular stomatitis Indiana virus / genetics
  • Vesicular stomatitis Indiana virus / immunology
  • Vesicular stomatitis Indiana virus / metabolism
  • Vesicular stomatitis Indiana virus / physiology*
  • Virus Replication / genetics


  • Cytokines
  • Interferon Type I
  • Interleukin-1
  • Membrane Glycoproteins
  • Myeloid Differentiation Factor 88
  • Tlr4 protein, mouse
  • Tlr7 protein, mouse
  • Toll-Like Receptor 4
  • Toll-Like Receptor 7