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

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135 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4464-4478
Number of pages15
JournalJournal of Clinical Investigation
Volume123
Issue number10
DOIs
Publication statusPublished - Oct 1 2013

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ASJC Scopus subject areas

  • Medicine(all)

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Waight, J. D., Netherby, C., Hensen, M. L., Miller, A., Hu, Q., Liu, S., ... Abrams, S. I. (2013). Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis. Journal of Clinical Investigation, 123(10), 4464-4478. https://doi.org/10.1172/JCI68189