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 2

Irf8-deficient mice harbor MDSC-like cells.

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Irf8-deficient mice harbor MDSC-like cells. (A) Ability of CD11b+Gr-1...
(A) Ability of CD11b+Gr-1+ cells isolated from WT or Irf8–/– mice to inhibit anti-CD3–stimulated T cells at the indicated cell densities (n = 3 determinations, *P < 0.02; T cells plus anti-CD3 mAb control, average cpm, 127,151). (B) Ability of purified CD11b+Gr-1+ cells from Irf8–/– mice to suppress alloreactive (H-2b anti–H-2d) T cell proliferation relative to the control, incubated with CD11b+Gr-1+ cells from WT mice. The CD11b+Gr-1+ cells matched the haplotype of the responder T cells and were tested at the indicated lymphocyte to myeloid cell ratios. Proliferation in A and B was measured through 3H-thymidine uptake and is representative of 2 separate experiments. (C) AT-3 tumor cells were co-mixed with or without CD11b+Gr-1+ cells derived from Irf8–/– mice, and tumor growth was recorded. The results represent the mean ± SEM (n = 8 recipient mice/group pooled from 2 separate experiments; *P = 0.002). (D) AT-3 tumor growth rate in WT versus Irf8–/– mice (n = 5 recipient mice/group; P = 0.02).