VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling.
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.
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Phonphimon
P
Wongthida
Rosa M
RM
Diaz
Feorillo
F
Galivo
Timothy
T
Kottke
Jill
J
Thompson
Alan
A
Melcher
Richard
R
Vile
D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000172:deficiency / Q000235:genetics; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D050130:Oncolytic Virotherapy / Q000379:methods*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000235:genetics; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D014779:Virus Replication / Q000235:genetics
D016207:Cytokines; D007370:Interferon Type I; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; C477038:Tlr7 protein, mouse; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7