Modulating the expression of IFN regulatory factor 8 alters the protumorigenic behavior of CD11b+Gr-1+ myeloid cells.
CD11b(+)Gr-1(+)-expressing cells, termed myeloid-derived suppressor cells, can mediate immunosuppression and tumor progression. However, the intrinsic molecular events that drive their protumorigenic behavior remain to be elucidated. Although CD11b(+)Gr-1(+) cells exist at low frequencies in normal mice, it also remains unresolved whether they are biologically distinct from those of tumor-bearing hosts. These objectives were investigated using CD11b(+)Gr-1(+) cells from both implantable (4T1) and autochthonous (mouse mammary tumor virus-polyomavirus middle T Ag (MMTV-PyMT)) mouse models of mammary carcinoma. Limited variation was observed in the expression of markers associated with immunoregulation between CD11b(+)Gr-1(+) cells of both tumor models, as well as with their respective controls (Cnt). Despite limited differences in phenotype, tumor-induced CD11b(+)Gr-1(+) cells were found to produce a more immunosuppressive cytokine profile than that observed by Cnt CD11b(+)Gr-1(+) cells. Furthermore, when admixed with tumor cells, CD11b(+)Gr-1(+) cells from tumor-bearing mice significantly enhanced neoplastic growth compared with counterpart cells from Cnt mice. However, the protumorigenic behavior of these tumor-induced CD11b(+)Gr-1(+) cells was significantly diminished when the expression of IFN regulatory factor 8, a key myeloid-associated transcription factor, was enhanced. The loss of this protumorigenic effect occurred independently of the host immune system and correlated with a CD11b(+)Gr-1(+) cytokine/chemokine production pattern that resembled cells from nontumor-bearing Cnt mice. Overall, our data indicate that 1) tumor-induced CD11b(+)Gr-1(+) cells from both cancer models were phenotypically similar, but biologically distinct from their nontumor-bearing counterparts and 2) modulation of IFN regulatory factor 8 levels in tumor-induced CD11b(+)Gr-1(+) cells can significantly abrogate their protumorigenic behavior, which may have important implications for cancer therapy.
Stewart
Trina J
TJ
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Liewehr
David J
DJ
Steinberg
Seth M
SM
Greeneltch
Kristy M
KM
Abrams
Scott I
SI
D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D039481:CD11b Antigen / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D011120:Polyomavirus / Q000235:genetics / Q000276:immunology; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000099185:Interferon Regulatory Factor-8
D014408:Biomarkers, Tumor; D039481:CD11b Antigen; D050835:Interferon Regulatory Factors; D019707:Receptors, Chemokine; D000099185:Interferon Regulatory Factor-8; C503133:Gr-1 protein, mouse