The Granulocyte Progenitor Stage Is a Key Target of IRF8-Mediated Regulation of Myeloid-Derived Suppressor Cell Production.

Autor:	Netherby CS; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263., Messmer MN; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263., Burkard-Mandel L; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263., Colligan S; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263., Miller A; Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263; and., Cortes Gomez E; Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263; and., Wang J; Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263; and., Nemeth MJ; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263., Abrams SI; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; scott.abrams@roswellpark.org.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2017 May 15; Vol. 198 (10), pp. 4129-4139. Date of Electronic Publication: 2017 Mar 29.
DOI:	10.4049/jimmunol.1601722
Abstrakt:	Alterations in myelopoiesis are common across various tumor types, resulting in immature populations termed myeloid-derived suppressor cells (MDSCs). MDSC burden correlates with poorer clinical outcomes, credited to their ability to suppress antitumor immunity. MDSCs consist of two major subsets, monocytic and polymorphonuclear (PMN). Intriguingly, the latter subset predominates in many patients and tumor models, although the mechanisms favoring PMN-MDSC responses remain poorly understood. Ordinarily, lineage-restricted transcription factors regulate myelopoiesis that collectively dictate cell fate. One integral player is IFN regulatory factor (IRF)-8, which promotes monocyte/dendritic cell differentiation while limiting granulocyte development. We recently showed that IRF8 inversely controls MDSC burden in tumor models, particularly the PMN-MDSC subset. However, where IRF8 acts in the pathway of myeloid differentiation to influence PMN-MDSC production has remained unknown. In this study, we showed that: 1) tumor growth was associated with a selective expansion of newly defined IRF8 lo granulocyte progenitors (GPs); 2) tumor-derived GPs had an increased ability to form PMN-MDSCs; 3) tumor-derived GPs shared gene expression patterns with IRF8 -/- GPs, suggesting that IRF8 loss underlies GP expansion; and 4) enforced IRF8 overexpression in vivo selectively constrained tumor-induced GP expansion. These findings support the hypothesis that PMN-MDSCs result from selective expansion of IRF8 lo GPs, and that strategies targeting IRF8 expression may limit their load to improve immunotherapy efficacy. (Copyright © 2017 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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