Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis
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
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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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 4

MDSC accumulation is diminished in Irf8-Tg mice.

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MDSC accumulation is diminished in Irf8-Tg mice. (A) Splenocyte counts...
(A) Splenocyte counts (on the right y axis) from AT-3 tumor–bearing WT mice or Irf8-Tg mice of the indicated founder line. The data are shown for mice with larger tumor volumes (>1,200 mm3) to illustrate the impact of Irf8 under the most advanced tumor conditions. *P < 0.003. (B) Relationship between tumor size and splenocyte number for all mice, including those with smaller tumor volumes (<1,200 mm3) to generate a broader curve (Spearman r value = 0.59; *P = 0.008 for WT; not significant for either Tg line). Each symbol represents a single mouse. (C) Quantification of CD11b+Gr-1+ cells from bone marrow of WT or Irf8-Tg mice with (TB) or without (NTB) tumor growth (>1,200 mm3). (D) Representative contour plots of Ly6C and Ly6G expression on the CD11b-gated splenic fraction. (E) Upper panel: quantification of splenic granulocytic and monocytic subsets using a gating strategy similar to that described in Supplemental Figure 1 (n = 4 mice each; in the case the Tg group, 3 from line 370 and 1 from line 371). Lower panel: tumor sizes in individual mice. (F) Granulocytic (left y axis) and monocytic (right y axis) MDSC subsets plotted in relation to their respective tumor sizes from E. *P < 0.04 for WT subsets; not significant for Tg subsets. The data are reported as the mean ± SEM for the number of mice or experiments shown.