title: The Granulocyte Progenitor Stage Is a Key Target of IRF8-Mediated Regulation of Myeloid-Derived Suppressor Cell Production.
abstract: 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 IRF8logranulocyte 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 IRF8loGPs, and that strategies targeting IRF8 expression may limit their load to improve immunotherapy efficacy.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.
authors.forename: Colleen S
authors.initials: CS
authors.lastname: Netherby
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Messmer
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.
authors.forename: Lauren
authors.initials: L
authors.lastname: Burkard-Mandel
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.
authors.forename: Sean
authors.initials: S
authors.lastname: Colligan
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263; and.
authors.forename: Austin
authors.identifier: 0000-0001-9739-8462
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263; and.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Cortes Gomez
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263; and.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.|Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Nemeth
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; scott.abrams@roswellpark.org.
authors.forename: Scott I
authors.identifier: 0000-0002-0966-6488
authors.initials: SI
authors.lastname: Abrams
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042381:Granulocyte Precursor Cells / Q000276:immunology / Q000502:physiology*; D006098:Granulocytes / Q000276:immunology; D006410:Hematopoiesis; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000503:physiopathology*; D051379:Mice; D009000:Monocytes / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology / Q000502:physiology*; D038042:Myelopoiesis; D009504:Neutrophils / Q000276:immunology; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8