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

Kristy M. Greeneltch, Monika Schneider, Seth M. Steinberg, David J. Liewehr, Trina J. Stewart, Kebin Liu, Scott I. Abrams

Research output: Contribution to journalArticle

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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-γ- 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.

Original languageEnglish (US)
Pages (from-to)10406-10416
Number of pages11
JournalCancer Research
Volume67
Issue number21
DOIs
StatePublished - Nov 1 2007

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Immunologic Monitoring
Growth
Neoplasms
Myelopoiesis
Apoptosis
Tumor Escape
Phenotype
Fas Ligand Protein
Hematologic Neoplasms
Myeloid Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
RNA Interference
Tumor Suppressor Genes
Innate Immunity
Natural Killer Cells
Population
Down-Regulation
Macrophages
Cell Proliferation
T-Lymphocytes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Greeneltch, K. M., Schneider, M., Steinberg, S. M., Liewehr, D. J., Stewart, T. J., Liu, K., & Abrams, S. I. (2007). Host immunosurveillance controls tumor growth via IFN regulatory factor-8-dependent mechanisms. Cancer Research, 67(21), 10406-10416. https://doi.org/10.1158/0008-5472.CAN-07-1228

Host immunosurveillance controls tumor growth via IFN regulatory factor-8-dependent mechanisms. / Greeneltch, Kristy M.; Schneider, Monika; Steinberg, Seth M.; Liewehr, David J.; Stewart, Trina J.; Liu, Kebin; Abrams, Scott I.

In: Cancer Research, Vol. 67, No. 21, 01.11.2007, p. 10406-10416.

Research output: Contribution to journalArticle

Greeneltch, KM, Schneider, M, Steinberg, SM, Liewehr, DJ, Stewart, TJ, Liu, K & Abrams, SI 2007, 'Host immunosurveillance controls tumor growth via IFN regulatory factor-8-dependent mechanisms', Cancer Research, vol. 67, no. 21, pp. 10406-10416. https://doi.org/10.1158/0008-5472.CAN-07-1228
Greeneltch, Kristy M. ; Schneider, Monika ; Steinberg, Seth M. ; Liewehr, David J. ; Stewart, Trina J. ; Liu, Kebin ; Abrams, Scott I. / Host immunosurveillance controls tumor growth via IFN regulatory factor-8-dependent mechanisms. In: Cancer Research. 2007 ; Vol. 67, No. 21. pp. 10406-10416.
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