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

Phonphimon Wongthida, Rosa M. Diaz, Feorillo Galivo, Timothy Kottke, Jill Thompson, Alan Melcher, Richard Vile

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)150-158
Number of pages9
JournalMolecular Therapy
Volume19
Issue number1
DOIs
StatePublished - Jan 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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