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

J Clin Invest. 2013 Oct;123(10):4464-78. doi: 10.1172/JCI68189. Epub 2013 Sep 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Disease-Free Survival
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interferon Regulatory Factors / genetics*
  • Interferon Regulatory Factors / metabolism
  • Kaplan-Meier Estimate
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / physiology*
  • Neoplasm Transplantation
  • STAT3 Transcription Factor / metabolism*
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction
  • Transcriptome
  • Tumor Burden

Substances

  • Interferon Regulatory Factors
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Stat3 protein, mouse
  • interferon regulatory factor-8

Associated data

  • GEO/GSE39228