Cytokine-armed vaccinia virus infects the mesothelioma tumor microenvironment to overcome immune tolerance and mediate tumor resolution.
Intratumoral (i.t.) administration of cytokine genes expressed by viral vectors represents a rational approach that induces cytokine secretion at the site they are needed, and i.t. vaccinia virus (VV) has shown promise in mesothelioma patients. However, we and others have shown that the mesothelioma tumor microenvironment includes macrophages, dendritic cells (DCs), and T cells. Therefore, we investigated which of these cell types are infected after exposure to VV or Fowlpox virus (FPV)-cytokine gene constructs. In vitro studies showed that mesothelioma tumor cells were resistant to FPV infection yet highly permissive to infection by VV vectors resulting in significant cytokine production and impaired proliferation. Macrophages secreted low levels of cytokine suggestive of resistance to overt infection. DCs transiently secreted virally derived cytokines, but did not mature during VV infection. VV inhibition of T cell proliferation was rescued by the interleukin (IL)-2 and IL-12 VV constructs. In vivo studies of murine mesotheliomas showed that i.t. injection of the parent VV could not hinder tumor progression. In contrast, the VV-cytokine constructs induced profound tumor regression. These data suggest that i.t. VV-cytokine gene constructs retard tumor growth by infecting mesothelioma cells and targeting the immune system through tumor-infiltrating DC and T cells.
Curtin University, School of Biomedical Sciences, Bentley, Perth, Western Australia, Australia.
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Jackaman
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Nelson
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005587:Fowlpox virus / Q000235:genetics / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D008654:Mesothelioma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology
D016207:Cytokines; D007376:Interleukin-2; D018664:Interleukin-12