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 6

Influence of Irf8 enhancement on tumor growth during immunosurveillance or immunotherapy.

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Influence of Irf8 enhancement on tumor growth during immunosurveillance ...
(A) Tumor growth rate of AT-3 cells in WT versus Irf8-Tg mice (n = 9 for WT and n = 10 for Tg line 370). (B) WT or Tg mice (line 370) were treated with either anti-Ly6G mAb or an isotype control after the tumors became palpable. The data are representative of 2 experiments (n = 10 mice/group). *P = 0.009 for differences in tumor growth rate between anti-Ly6G–treated Irf8-Tg mice versus all other cohorts. (C) As in B, except that the mice were treated with either anti–CTLA-4 mAb or an isotype control. The data are representative of 2 separate experiments (n = 5 mice/group). *P < 0.04 for differences in tumor sizes between anti–CTLA-4–treated and vehicle-treated Irf8-Tg mice at days 18, 21, 27, and 30; P < 0.05 at day 15. (D) Tumor growth rate of 4T1 cells in WT versus Irf8-Tg mice (Tg line 370). (E) Spontaneous lung metastasis was quantified at endpoint tumor volumes for mice in D (n = 12 WT; n = 14 Tg). (E) H&E-stained lung tissues were used to quantify metastasis. (F) Representative H&E-stained lung images (left; original magnification, ×20) and representative images of anti–Gr-1 staining (1 of 3 mice tested), analyzed through IHC (right; original magnification, ×400). The arrows indicate examples of discrete foci; Tu, tumor; Pa, parenchyma. H&E analysis comfirmed myeloid morphology. (G) Quantification of IHC data in F, based on the average number of stained cells per high-power field (×400) from 5 random sections of each slide. The data represent the mean ± SEM of 3 mice per group.