Distinct roles for IFN regulatory factor (IRF)-3 and IRF-7 in the activation of antitumor properties of human macrophages.
When properly activated, macrophages can be tumoricidal, thus making them attractive additions to standard cancer therapies. To this end, tolerance and activity of human autologous IFN-gamma-activated macrophages, produced in large scale for clinical use (MAK cells), have been assessed in pilot trials in cancer patients. In the present study, we tested the hypothesis that activation of IFN regulatory factor (IRF)-3 and IRF-7, with subsequent type I IFN production, may be involved in the acquisition of new antitumor functions by macrophages. Adenoviral vectors were generated for the delivery of constitutively active forms of IRF-3 (Ad-IRF-3) or IRF-7 (Ad-IRF-7) into primary human macrophages. Cell death was observed in Ad-IRF-3-transduced macrophages, whereas Ad-IRF-7-transduced macrophages produced type I IFNs and displayed increased expression of genes encoding tumor necrosis factor (TNF)-related apoptosis-inducing ligand, interleukin (IL)-12, IL-15, and CD80, persisting for at least 96 hours. Expression of iNOS, TNF-alpha, FasL, IL-1, and IL-6 genes was unaltered by Ad-IRF-7 transduction. Interestingly, Ad-IRF-3 or Ad-IRF-7 transduction negatively regulated the transcription of protumorigenic genes encoding vascular endothelial growth factor and matrix metalloproteinase-2. Furthermore, Ad-IRF-7-transduced macrophages exerted a cytostatic activity on different cancer cell lines, including SK-BR-3, MCF-7, and COLO-205; the latter cells were shown previously to be insensitive to MAK cells. In conclusion, transduction of active forms of IRF-3 or IRF-7 differentially modulate the apoptotic and antitumor properties of primary macrophages, with active IRF-7 leading to the acquisition of novel antitumor effector functions.
Romieu-Mourez
Raphaëlle
R
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
Solis
Mayra
M
Nardin
Alessandra
A
Goubau
Delphine
D
Baron-Bodo
Véronique
V
Lin
Rongtuan
R
Massie
Bernard
B
Salcedo
Margarita
M
Hiscott
John
J
D017209:Apoptosis; D018122:B7-1 Antigen / Q000235:genetics; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000502:physiology*; D007370:Interferon Type I / Q000235:genetics; D019409:Interleukin-15 / Q000235:genetics; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D014161:Transduction, Genetic
D018122:B7-1 Antigen; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D019409:Interleukin-15; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand