CASE REPORTS
Innate immune immunity and viral therapy of cancer
Glen N. Barber
Activation of host innate immune responses following virus infection is largely mediated by viral dsRNA, the mechanisms of which remain to be fully determined. We have recently reported that murine embryonic fibroblasts (MEFs) lacking the death adaptor molecule FADD are defective in double-stranded RNA (dsRNA)-activated antiviral gene expression, including Type I interferon (IFN), and thus predisposed to virus infection. The dsRNA signaling pathway incorporating FADD was found to be largely independent of Toll-like Receptor (TLR)-3, tumour-necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and the dsRNA-dependent protein kinase, PKR, though obligated TBK1 activation of IRF3. The requirement for FADD in innate immune responses is evocative of the imd pathway in Drosophila, which involves an imd/dFADD complex that responds to bacteria infection by activating the transcription of anti-microbial genes. Accordingly, cells lacking the mammalian imd homologue, receptor interacting protein 1 (RIP) were also found to be defective in Type I IFN induction and antiviral activity in response to virus/dsRNA, similar to FADD deficient cells. This data indicate the existence of a key intracellular dsRNA/virus recognition pathway in mammalian cells, which is central for the induction Type I IFN and the activation of other important primary innate immune response genes.
In addition, our laboratory has recently shown that vesicular stomatitis virus, VSV, a relatively non-pathogenic, negative-stranded RNA virus, can selectively induce the cytolysis of malignant cells, through the induction of apoptotic cell death. VSV appears able to selectively replicate in transformed cells since these hosts exhibit the hallmarks of a flawed interferon (IFN) system, which is essential for preventing VSV replication. In part, these cellular flaws may include prevalent defects in the regulation of cellular translation. Wild type VSV causes significant tumor regression when administered at sites distal from the tumor, when delivered intravenously, or against syngeneic tumors in immunocompetent hosts. The simple genetic constitution of VSV, lack of any known transforming properties, well studied immunobiology and the ability to genetically manipulate this virus affords an ideal opportunity to further enhance the oncolytic potential of this generally innocuous organism. Accordingly, we have constructed recombinant VSVs that carried cytokines such as IL-4, IL-12 or the Type I or II interferons. We have determined that such viruses were not only viable but synthesized their heterologous products to extremely high levels. In addition, all engineered viruses exhibited greatly increased attenuation, more potent oncolytic activity against metastatic disease in immunocompetent animals than the wild-type virus and were able to stimulate specific anti-tumor CTL responses. Collectively, our data demonstrates that VSV expressing immunodulatory genes could provide a promising approach to cancer therapy and be useful tools for examining mechanisms of tumorigenesis.
Publication Dates
-
Publication in this collection
06 Jan 2006 -
Date of issue
Oct 2005
