Host immunosurveillance controls tumor growth via IFN regulatory factor-8 dependent mechanisms.
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.
Greeneltch
Kristy M
KM
Laboratory of Tumor Immunology and Biology, Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, MD 20892-1402, USA.
Schneider
Monika
M
Steinberg
Seth M
SM
Liewehr
David J
DJ
Stewart
Trina J
TJ
Liu
Kebin
K
Abrams
Scott I
SI
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053222:Fas Ligand Protein / Q000502:physiology; D005260:Female; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D019139:Tumor Escape; D019014:fas Receptor / Q000502:physiology; D000099185:Interferon Regulatory Factor-8
D053222:Fas Ligand Protein; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D019014:fas Receptor; D000099185:Interferon Regulatory Factor-8