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Cancer Res. 2016 Jan 1;76(1):35-42. doi: 10.1158/0008-5472.CAN-15-0869. Epub 2015 Nov 16.

M-CSF and GM-CSF Receptor Signaling Differentially Regulate Monocyte Maturation and Macrophage Polarization in the Tumor Microenvironment.

Author information

1
Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
2
Department of Medicine III, RWTH University-Hospital Aachen, Aachen, Germany.
3
Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, VIB, Ghent, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
4
Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium. jvangind@vub.ac.be.

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.

PMID:
26573801
DOI:
10.1158/0008-5472.CAN-15-0869
[Indexed for MEDLINE]
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