Cytokine-armed vaccinia virus infects the mesothelioma tumor microenvironment to overcome immune tolerance and mediate tumor resolution.

Abstract:

: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.

journal_name

Cancer Gene Ther

journal_title

Cancer gene therapy

authors

Jackaman C,Nelson DJ

doi

10.1038/cgt.2009.85

subject

Has Abstract

pub_date

2010-06-01 00:00:00

pages

429-40

issue

6

eissn

0929-1903

issn

1476-5500

pii

cgt200985

journal_volume

17

pub_type

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