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Modulating the Expression of IFN Regulatory Factor 8 Alters the Protumorigenic Behavior of CD11b⁺Gr-1⁺ Myeloid Cells¹

Trina J. Stewart^*, David J. Liewehr, Seth M. Steinberg, Kristy M. Greeneltch^* and Scott I. Abrams^2,*,

^* Laboratory of Tumor Immunology and Biology and Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. S.I.A. was also supported in part by Roswell Park Cancer Institute Institutional Funding.

² Address correspondence and reprint requests to Dr. Scott I. Abrams at the current address: Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail address: scott.abrams{at}roswellpark.org

³ Abbreviations used in this paper used in this paper: MDSC, myeloid-derived suppressor cell; TDF, tumor-derived factor; IRF-8, IFN regulatory factor 8; MTAG, middle T Ag; MMTV-PyMT, mouse mammary tumor virus-polyomavirus MTAG; Tg, transgenic; VEGF, vascular endothelia growth factor; IP-10, FN--inducible protein 10; KC, keratinocyte-derived chemokine; Cnt, control; MTAG, middle T Ag.