Host immunosurveillance controls tumor growth via IFN regulatory factor-8 dependent mechanisms.

Abstract

IFN regulatory factor (IRF)-8 plays an important role in normal myelopoiesis. The loss of IRF-8 in myeloid cells results in a chronic myelogenous leukemia-like syndrome, suggesting that IRF-8 behaves as a tumor suppressor gene in certain hematopoietic malignancies. We have been investigating the molecular determinants of solid tumor progression, with an emphasis on apoptotic resistance. Recently, we showed that IRF-8 expression was directly correlated with Fas-mediated apoptosis, and inversely related to malignant phenotype. However, the functional role of IRF-8 in solid tumors is unresolved. We stably silenced IRF-8 expression via RNA interference in IRF-8-expressing mouse tumor cells, and evaluated them for changes in apoptotic phenotype and malignant behavior. Apoptosis induced by Fas engagement or irradiation was markedly reduced in IRF-8-deficient tumor cells, despite unaltered proliferation, cell surface Fas, or MHC class I expression. Moreover, in syngeneic immunocompetent mice, IRF-8-deficient tumor cells grew more aggressively than their control counterparts. However, in IFN-gamma- or Fas ligand-deficient mice, but not T cell-deficient mice, both control and IRF-8-deficient tumor populations grew similarly. Furthermore, both tumor populations grew similarly in mice with defects in innate immunity. Although subsequent studies precluded a role for natural killer cells, immunohistochemical analysis supported the involvement of macrophages. Overall, our findings show that IRF-8 expression in solid tumor cells is important for efficient host immunosurveillance and response to apoptotic stimuli. Therefore, IRF-8 down-regulation may represent a previously unrecognized tumor escape mechanism that facilitates tumor progression. Conversely, strategies aimed at up-regulating or restoring IRF-8 expression in neoplastic cells may improve therapeutic efficacy.

• Authors: Kristy M Greeneltch, Monika Schneider, Seth M Steinberg, David J Liewehr, Trina J Stewart, Kebin Liu, Scott I Abrams
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 21 Pg. 10406-16 (Nov 01 2007) ISSN: 1538-7445 [Electronic] United States
• PMID: 17974984 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Fas Ligand Protein
• Interferon Regulatory Factors
• fas Receptor
• interferon regulatory factor-8
• Interferon-gamma

Topics

• Animals
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Fas Ligand Protein (physiology)
• Female
• Immunity, Innate
• Interferon Regulatory Factors (antagonists & inhibitors, genetics, physiology)
• Interferon-gamma (physiology)
• Killer Cells, Natural (immunology)
• Mice
• Mice, Inbred BALB C
• Neoplasms, Experimental (immunology, pathology)
• Tumor Escape
• fas Receptor (physiology)