Interferon regulatory factor 8 mediates tumor-induced inhibition of antigen processing and presentation by dendritic cells |
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Authors: | Irina L Tourkova Galina V Shurin " target="_blank">Soldano Ferrone " target="_blank">Michael R Shurin |
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Institution: | (1) Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA;(2) Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA;(3) Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA;(4) University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA;(5) Department of Pathology, Division of Clinical Immunopathology, University of Pittsburgh Medical Center, 5725 CHP MT, 200 Lothrop Street, Pittsburgh, PA 15213, USA; |
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Abstract: | Introduction Suppression of dendritic cells (DCs) is a crucial mechanism by which tumor cells escape immune recognition and elimination.
We have recently reported that MHC class I antigen processing machinery (APM) component expression in human DCs is down-regulated
by tumor-derived gangliosides. However, the molecular mechanisms underlying this abnormality were not identified. Thus, the
aim of this work was to analyze the role of interferon regulatory factor 8 (IRF-8) in APM protein expression and the antigen
presenting capacity of DCs developed in the tumor microenvironment.
Results We demonstrate that the expression of several MHC class I APM components, including delta, MB-1, LMP-10, ERp57, and tapasin,
is significantly decreased in murine DCs generated in the presence of prostate cancer cells. APM component down-regulation
was associated with decreased ability of DCs to present model antigen to antigen-specific T cells. Notable, impaired antigen-presenting
activity of DCs co-cultured with tumor cells was accompanied by decreased levels of IRF-8. Transduction of DCs with the silencing
RNA for the IRF-8 gene also led to reduced expression of APM components in DCs and decreased antigen presenting function.
Conclusion Together, our data suggest that tumor-induced inhibition of antigen processing and presenting function of DCs is mediated
by IRF-8, a member of the interferon regulatory factor family. These results provide a new molecular target for optimizing
the generation of efficient DC vaccines for cancer therapy. |
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Keywords: | Antigen-processing machinery Dendritic cells IRF-8 Prostate cancer |
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