| VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling. | |
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MedLine Citation:
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PMID: 20959810 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Phonphimon Wongthida; Rosa M Diaz; Feorillo Galivo; Timothy Kottke; Jill Thompson; Alan Melcher; Richard Vile |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-19 |
Journal Detail:
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Title: Molecular therapy : the journal of the American Society of Gene Therapy Volume: 19 ISSN: 1525-0024 ISO Abbreviation: Mol. Ther. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-04 Completed Date: 2011-04-14 Revised Date: 2012-01-04 |
Medline Journal Info:
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Nlm Unique ID: 100890581 Medline TA: Mol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 150-8 Citation Subset: IM |
Affiliation:
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Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line, Tumor Cytokines / genetics, immunology Dendritic Cells / immunology Immunity, Innate / immunology Interferon Type I / immunology, metabolism Interleukin-1 / deficiency, genetics Melanoma, Experimental / immunology, metabolism, therapy*, virology Membrane Glycoproteins / deficiency, genetics Mice Mice, Inbred C57BL Myeloid Differentiation Factor 88 / genetics, metabolism* Oncolytic Virotherapy / methods* Signal Transduction T-Lymphocytes / immunology Toll-Like Receptor 4 / deficiency, genetics Toll-Like Receptor 7 / deficiency, genetics Vesicular stomatitis Indiana virus / genetics, immunology, metabolism, physiology* Virus Replication / genetics |
| Grant Support | |
ID/Acronym/Agency:
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CA107082/CA/NCI NIH HHS; CA130878/CA/NCI NIH HHS; CA132734/CA/NCI NIH HHS; R01 CA107082-06/CA/NCI NIH HHS; R01 CA107082-07/CA/NCI NIH HHS; R01 CA130878-03/CA/NCI NIH HHS; R01 CA130878-04/CA/NCI NIH HHS; R01 CA132734-04/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/Interferon Type I; 0/Interleukin-1; 0/Membrane Glycoproteins; 0/Myeloid Differentiation Factor 88; 0/Tlr4 protein, mouse; 0/Tlr7 protein, mouse; 0/Toll-Like Receptor 4; 0/Toll-Like Receptor 7 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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