Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis
Jeremy D. Waight, … , Kebin Liu, Scott I. Abrams
Jeremy D. Waight, … , Kebin Liu, Scott I. Abrams
Published September 16, 2013
Citation Information: J Clin Invest. 2013;123(10):4464-4478. https://doi.org/10.1172/JCI68189.
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Research Article Immunology

Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis

Abstract

Myeloid-derived suppressor cells (MDSCs) comprise immature myeloid populations produced in diverse pathologies, including neoplasia. Because MDSCs can impair antitumor immunity, these cells have emerged as a significant barrier to cancer therapy. Although much research has focused on how MDSCs promote tumor progression, it remains unclear how MDSCs develop and why the MDSC response is heavily granulocytic. Given that MDSCs are a manifestation of aberrant myelopoiesis, we hypothesized that MDSCs arise from perturbations in the regulation of interferon regulatory factor–8 (IRF-8), an integral transcriptional component of myeloid differentiation and lineage commitment. Overall, we demonstrated that (a) Irf8-deficient mice generated myeloid populations highly homologous to tumor-induced MDSCs with respect to phenotype, function, and gene expression profiles; (b) IRF-8 overexpression in mice attenuated MDSC accumulation and enhanced immunotherapeutic efficacy; (c) the MDSC-inducing factors G-CSF and GM-CSF facilitated IRF-8 downregulation via STAT3- and STAT5-dependent pathways; and (d) IRF-8 levels in MDSCs of breast cancer patients declined with increasing MDSC frequency, implicating IRF-8 as a negative regulator in human MDSC biology. Together, our results reveal a previously unrecognized role for IRF-8 expression in MDSC subset development, which may provide new avenues to target MDSCs in neoplasia.

Authors

Jeremy D. Waight, Colleen Netherby, Mary L. Hensen, Austin Miller, Qiang Hu, Song Liu, Paul N. Bogner, Matthew R. Farren, Kelvin P. Lee, Kebin Liu, Scott I. Abrams

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Figure 1

Irf8 expression is downregulated in tumor-induced MDSC subsets.

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Irf8 expression is downregulated in tumor-induced MDSC subsets. Irf8 ...
Irf8 mRNA levels in purified myeloid subsets from spleen of non-tumor-bearing or 4T1 (A) or AT-3 (B) tumor–bearing mice (≥1,000 mm3). The gating strategy for MDSC subset purification is shown in Supplemental Figure 1. Irf8 mRNA levels were measured through qPCR (n = 3 separate mice/group, *P < 0.01) and are representative of two separate experiments. For both panels, the data are expressed as the mean ± SEM of the fold changes relative to the first bar set at 1. (C) Upper panel: quantification of total splenocytes from Irf8–/– or WT littermate controls (8–10 weeks of age) (n = 5 each, *P < 0.01). Lower panel: CD11b and Gr-1 coexpression on splenocytes from Irf8–/– mice versus age-matched WT controls (n = 3 mice each, *P < 0.002). (D) Representative contour plot of Ly6C and Ly6G expression in the gated CD11b+ cells from WT and Irf8–/– mice in C. (E) Quantification of the percentages of granulocytic and monocytic subsets (*P < 0.003). (F) Total numbers of monocytic and granulocytic cells (*P < 0.001).