Interferon regulatory factor-8 modulates the development of tumour-induced CD11b+Gr-1+ myeloid cells
MetadataShow full item record
Tumor-induced myeloid-derived suppressor cells (MDSC) promote immune suppression and mediate tumor progression. However, the molecular basis for the generation of MDSC, which in mice co-express the CD11b+ and Gr-1+ cell surface markers remains unclear. Because CD11b+Gr-1+ cells expand during progressive tumor growth, this suggests that tumor-induced events alter signaling pathways that affect normal myeloid cell development. Interferon regulatory factor-8 (IRF-8), a member of the IFN-? regulatory factor family, is essential for normal myelopoiesis. We therefore examined whether IRF-8 modulated tumor-induced CD11b+Gr-1+ cell development or accumulation using both implantable (4T1) and transgenic (MMTV-PyMT) mouse models of mammary tumor growth. In the 4T1 model, both splenic and bone marrow-derived CD11b+Gr-1+ cells of tumor-bearing mice displayed a marked reduction in IRF-8 expression compared to control populations. A causal link between IRF-8 expression and the emergence of tumor-induced CD11b+Gr-1+ cells was explored in vivo using a double transgenic (dTg) mouse model designed to express transgenes for both IRF-8 and mammary carcinoma development. Despite the fact that tumor growth was unaffected, splenomegaly, as well as the frequencies and absolute numbers of CD11b+Gr-1+ cells were significantly lower in dTg mice when compared with single transgenic tumorbearing mice. Overall, these data reveal that IRF-8 plays an important role in tumorinduced development and/or accumulation of CD11b+Gr-1+ cells, and establishes a molecular basis for the potential manipulation of these myeloid populations for cancer therapy.
Journal of Cellular and Molecular Medicine
© 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. This is the author-manuscript version of the paper. Reproduced in accordance with the copyright policy of the publisher. The definitive version is available at http://onlinelibrary.wiley.com/