M-CSF and GM-CSF receptor signaling differentially affect the maturation of monocytes and the polarization of macrophage subsets in the tumor microenvironment

Identification: 2018


Description

M-CSF and GM-CSF receptor signaling differentially affect the maturation of monocytes and the polarization of macrophage subsets in the tumor microenvironment

Eva Van Overmeire1,2, Benoît Stijlemans1,2, Felix Heymann3, Jiri Keirsse1,2, Yannick Morias1,2, Yvon Elkrim1,2, Lea Brys1,2, Chloé Abels1,2, Qods Lahmar1,2, Can Ergen3, Lars Vereecke4,5, Frank Tacke3, Patrick De Baetselier1,2, Jo A Van Ginderachter1,2*, and Damya Laoui1,2*

1Laboratory of Myeloid Cell Immunology, VIB Inflammation Research Center, Ghent, Belgium; 2Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; 3Department of Medicine III, RWTH University-Hospital Aachen, Aachen, Germany; 4Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, VIB, Ghent, Belgium; 5Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
*Shared senior authorship

Tumors contain a heterogeneous myeloid fraction, encompassing discrete MHC-IIhi and MHC-IIlo tumor-associated macrophage (TAM) subpopulations, which originate from Ly6Chi monocytes. However, the mechanisms regulating the numbers and the phenotype of distinct TAM subsets remain unknown.

Here, we showed that treatment of tumor-bearing mice with a blocking anti-M-CSFR mAb resulted in a reduction of mature TAM in different tumor models, by impairing the recruitment, extravasation, proliferation and maturation of their Ly6Chi monocytic precursors. At the macrophage level, M-CSFR signaling blockade caused a shift in the MHC-IIlo/MHC-IIhi TAM balance in favor of the latter due to a preferential differentiation of Ly6Chi monocytes towards MHC-IIhi TAM. In addition, M-CSFR signaling appeared to be crucial in shaping the MHC-IIlo TAM phenotype, since genes, proteins and functions associated with MHC-IIlo TAM were downregulated upon M-CSFR blockade. Conversely, GM-CSFR had no role in the recruitment or intratumoral differentiation of Ly6Chi monocytes, since the mononuclear tumor infiltrate and relative abundance of TAM subsets was unaltered in GM-CSFR-deficient mice. However, GM-CSFR signaling played an important role in the fine-tuning of the MHC-IIhi phenotype.

Overall, our data uncover the multifaceted and opposing roles of M-CSFR and GM-CSFR signaling in determining the phenotype of macrophage subsets in tumors.

Credits

Credits: None available.

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