Visit our Expo - Redox and Inflammation signaling 2012

Distinct roles of IRF-3 and IRF-7 in the activation of anti-tumor properties of human
macrophages
Mayra Solis 1,* Raphaëlle Romieu-Mourez 1,* , Alessandra Nardin 2,* , Véronique Baron-
Bodo 2 , Delphine Goubau 1 , Bernard Massie 3 , Margarita Salcedo 2 and John Hiscott 1 .
* R.R-M, M.S. and A.N. contributed equally to this work 1 Terry Fox Molecular Oncology
Group, Lady Davis Institute McGill University, Montreal Canada H3T 1E2 2 IDM, Paris
France 3 Biotechnology Research Institute, Montreal Canada H4P 2R2
Type I interferons (IFN-alpha, –beta) exert strong antiviral, antiproliferative and
antiangiogenic effects and are widely used in clinical settings as adjuvants for therapy against
cancer. IFN-beta induction requires the activation of latent transcription factors, including the
interferon regulating factor (IRF)-3, NF-!B and ATF-2/c-Jun. Secretion of the newly
produced IFN-beta and binding to cognate adjacent type I IFN receptors induces transcription
of the irf7 gene. IRF-7 induces the expression of delayed IFN-alpha genes and elicits the full
induction of type I IFN production. When properly activated, macrophages can be
tumoricidal, thus making attractive additions to standard cancer therapies. Tolerance and
activity of human autologous IFN-gamma-activated macrophages, (MAK ® cells), have been
assessed in pilot trials in cancer patients. Here, we tested the hypothesis that activation of
IRF-3 and IRF-7, with subsequent type I IFN production, may be involved in the acquisition
of new antitumor functions by macrophages. We generated adenoviral vectors for the delivery
of constitutive active mutants of IRF-3 (Ad-F3) or IRF-7 (Ad-F7) into primary human
macrophages. Rapid cell death was observed in Ad-F3- transduced macrophages, whereas
Ad-F7-transduction produced type I IFNs and displayed increased expression of genes
encoding TRAIL, IL-12, IL-15 and CD80, persisting for at least 72 hours. Expression of
iNOS, TNF-alpha, FasL, IL-1 and IL-6 genes was unaltered by Ad-F7 transduction. In
addition, Ad-F3 and Ad-F7 transduction appeared to negatively regulate the transcription of
the pro-tumorigenic genes encoding IL-8, VEGF or MMP-2. Ad-F7- expressing macrophages
exerted a cytostatic activity on SK-BR3, MCF-7 and COLO-205 cancer cell lines. The latter
cells were previously shown to be insensitive to the action of non-activated macrophages or
MAK cells. In conclusion, transduction of active forms of IRF-3 or IRF-7 appears to
differentially regulate the apoptosis and the antitumor properties of primary macrophages,
with IRF-7 active mutant leading to the acquisition of novel anti-tumor effector functions.
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