Journal
JOURNAL OF IMMUNOLOGY
Volume 183, Issue 1, Pages 117-128Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0804132
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Funding
- National Institutes of Health
- National Cancer Institute
- Center for Cancer Research
- Roswell Park Cancer Institute
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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 Cut 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. The Journal of Immunology 2009, 183: 117-128.
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