Interferon regulatory factor-8 modulates the development of tumour-induced CD11b+Gr-1+ myeloid cells.
Tumour-induced myeloid-derived suppressor cells (MDSC) promote immune suppression and mediate tumour 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 tumour growth, this suggests that tumour-induced events alter signalling pathways that affect normal myeloid cell development. Interferon regulatory factor-8 (IRF-8), a member of the IFN-gamma regulatory factor family, is essential for normal myelopoiesis. We therefore examined whether IRF-8 modulated tumour-induced CD11b(+)Gr-1(+) cell development or accumulation using both implantable (4T1) and transgenic (MMTV-PyMT) mouse models of mammary tumour growth. In the 4T1 model, both splenic and bone marrow-derived CD11b(+)Gr-1(+) cells of tumour-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 tumour-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 tumour 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 tumour-bearing mice. Overall, these data reveal that IRF-8 plays an important role in tumour-induced 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.
Stewart
Trina J
TJ
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Greeneltch
Kristy M
KM
Reid
Julia E
JE
Liewehr
David J
DJ
Steinberg
Seth M
SM
Liu
Kebin
K
Abrams
Scott I
SI
D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis*; D002277:Carcinoma / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099185:Interferon Regulatory Factor-8
D039481:CD11b Antigen; D050835:Interferon Regulatory Factors; D019707:Receptors, Chemokine; D000099185:Interferon Regulatory Factor-8; C503133:Gr-1 protein, mouse