title: M-CSF and GM-CSF Receptor Signaling Differentially Regulate Monocyte Maturation and Macrophage Polarization in the Tumor Microenvironment.
abstract: Tumors contain a heterogeneous myeloid fraction comprised of discrete MHC-II(hi) and MHC-II(lo) tumor-associated macrophage (TAM) subpopulations that originate from Ly6C(hi) monocytes. However, the mechanisms regulating the abundance and phenotype of distinct TAM subsets remain unknown. Here, we investigated the role of macrophage colony-stimulating factor (M-CSF) in TAM differentiation and polarization in different mouse tumor models. We demonstrate that treatment of tumor-bearing mice with a blocking anti-M-CSFR monoclonal antibody resulted in a reduction of mature TAMs due to impaired recruitment, extravasation, proliferation, and maturation of their Ly6C(hi) monocytic precursors. M-CSFR signaling blockade shifted the MHC-II(lo)/MHC-II(hi) TAM balance in favor of the latter as observed by the preferential differentiation of Ly6C(hi) monocytes into MHC-II(hi) TAMs. In addition, the genetic and functional signatures of MHC-II(lo) TAMs were downregulated upon M-CSFR blockade, indicating that M-CSFR signaling shapes the MHC-II(lo) TAM phenotype. Conversely, granulocyte macrophage (GM)-CSFR had no effect on the mononuclear tumor infiltrate or relative abundance of TAM subsets. However, GM-CSFR signaling played an important role in fine-tuning the MHC-II(hi) phenotype. Overall, our data uncover the multifaceted and opposing roles of M-CSFR and GM-CSFR signaling in governing the phenotype of macrophage subsets in tumors, and provide new insight into the mechanism of action underlying M-CSFR blockade.
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Van Overmeire
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Benoît
authors.initials: B
authors.lastname: Stijlemans
authors.affiliation: Department of Medicine III, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Heymann
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Jiri
authors.initials: J
authors.lastname: Keirsse
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Morias
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Yvon
authors.initials: Y
authors.lastname: Elkrim
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Lea
authors.initials: L
authors.lastname: Brys
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Chloé
authors.initials: C
authors.lastname: Abels
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Qods
authors.initials: Q
authors.lastname: Lahmar
authors.affiliation: Department of Medicine III, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Can
authors.initials: C
authors.lastname: Ergen
authors.affiliation: Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, VIB, Ghent, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Lars
authors.initials: L
authors.lastname: Vereecke
authors.affiliation: Department of Medicine III, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: De Baetselier
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium. jvangind@vub.ac.be.
authors.forename: Jo A
authors.initials: JA
authors.lastname: Van Ginderachter
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Damya
authors.initials: D
authors.lastname: Laoui
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D005260:Female; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D016184:Receptors, Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D016184:Receptors, Colony-Stimulating Factor; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor