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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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 7

Irf8 enhancement slows autochthonous tumor growth.

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Irf8 enhancement slows autochthonous tumor growth. (A) Tumor growth r...
(A) Tumor growth rate in double-Tg versus single-Tg mice, as determined after tracking the single largest tumor. Each symbol denotes a tumor measurement in a single mouse over time (n = 13 mice each; all Irf8-Tg mice from line 370). (B) Kaplan-Meier plot of the data in A, based on time to progression to approximately 50% of maximal tumor growth as a surrogate endpoint. (C) Each data point represents flow analysis of the indicated myeloid subset from single-Tg or double-Tg mice at endpoint. (D) Myeloid/tumor admixture experiments, as in Figure 2. AT-3 cells were mixed with splenic CD11b+Gr-1+ cells recovered from single-Tg, double-Tg, or non-tumor-bearing mice (WT), and tumor growth was recorded. The cells from single-Tg mice, but not those of double-Tg mice, showed a significant (*P < 0.001) increase in the AT-3 tumor growth rate relative to cells from WT mice (n = 5 mice/group; one of 2 separate experiments). The data are expressed as the mean ± SEM for the indicated number of mice. (E) Quantification of lung metastasis using histology (termed cohort 1) or CD11b+Gr-1+ cell frequency using flow cytometry analysis of total lung digests (termed cohort 2) from single-Tg or double-Tg mice. NTB, non-tumor-bearing WT mice. Both cohorts were matched based on age and primary tumor burden, as indicated in Results. (F) Representative H&E-stained images of metastatic foci in MTAG mice (upper left, original magnification, ×40; upper right, original magnification, ×100) and flow plots of CD11b+Gr-1+ cell populations (bottom panel).