This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Greeneltch, K. M. Articles by Abrams, S. I. Search for Related Content PubMed PubMed Citation Articles by Greeneltch, K. M. Articles by Abrams, S. I.

Host Immunosurveillance Controls Tumor Growth via IFN Regulatory Factor-8–Dependent Mechanisms

¹ Laboratory of Tumor Immunology and Biology, ² Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, Maryland; and ³ Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia

Requests for reprints: Scott I. Abrams, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Building 10, Room 5B46, 10 Center Drive, Bethesda, MD 20892-1402. Phone: 301-496-4343; Fax: 301-496-2756; E-mail: sa47z{at}nih.gov.

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-– 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. [Cancer Res 2007;67(21):10406–16]

This article has been cited by other articles:

				I. N. Buhtoiarov, A. L. Rakhmilevich, L. L. Lanier, E. A. Ranheim, and P. M. Sondel Naive Mouse Macrophages Become Activated following Recognition of L5178Y Lymphoma Cells via Concurrent Ligation of CD40, NKG2D, and CD18 Molecules J. Immunol., February 15, 2009; 182(4): 1940 - 1953. [Abstract] [Full Text] [PDF]

				D. Yang, S. Wang, C. Brooks, Z. Dong, P. V. Schoenlein, V. Kumar, X. Ouyang, H. Xiong, G. Lahat, A. Hayes-Jordan, et al. IFN Regulatory Factor 8 Sensitizes Soft Tissue Sarcoma Cells to Death Receptor-Initiated Apoptosis via Repression of FLICE-like Protein Expression Cancer Res., February 1, 2009; 69(3): 1080 - 1088. [Abstract] [Full Text] [PDF]

				J. M. McGough, D. Yang, S. Huang, D. Georgi, S. M. Hewitt, C. Rocken, M. Tanzer, M. P.A. Ebert, and K. Liu DNA Methylation Represses IFN-{gamma}-Induced and Signal Transducer and Activator of Transcription 1-Mediated IFN Regulatory Factor 8 Activation in Colon Carcinoma Cells Mol. Cancer Res., December 1, 2008; 6(12): 1841 - 1851. [Abstract] [Full Text] [PDF]