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 5

Intratumoral MDSC accumulation is also diminished in Irf8-Tg mice.

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Intratumoral MDSC accumulation is also diminished in Irf8-Tg mice. Flo...
Flow analysis of the indicated myeloid populations from primary tumor tissue of WT or Irf8-Tg mice at endpoint, as shown in Figure 4, A or C. Total live cells were first gated on the CD45+ leukocyte fraction. The gated CD45+ fraction was then plotted in relation to the myeloid markers shown in a manner similar to that in Supplemental Figure 1. The data are illustrated for total MDSCs (A), MDSC subsets (B and C), macrophages (D), and total DCs (E). (F) Ability of CD11b+Gr-1+ cells from AT-3 tumor–bearing WT or AT-3 tumor–bearing Irf8-Tg mice to suppress T cell proliferation in response to immobilized anti-CD3 mAb. T cells (1 × 105/well) and CD11b+Gr-1+ cells (5 × 104/well) (n = 3 determinations; *P < 0.01; T cells + anti-CD3 mAb without any CD11b+Gr-1+ cells, 23,212 ± 1,865).