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 Overmeire^1,2, Benoît Stijlemans^1,2, Felix Heymann³, Jiri Keirsse^1,2, Yannick Morias^1,2, Yvon Elkrim^1,2, Lea Brys^1,2, Chloé Abels^1,2, Qods Lahmar^1,2, Can Ergen³, Lars Vereecke^4,5, Frank Tacke³, Patrick De Baetselier^1,2, Jo A Van Ginderachter^1,2*, and Damya Laoui^1,2*

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-II^hi and MHC-II^lo tumor-associated macrophage (TAM) subpopulations, which originate from Ly6C^hi 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 Ly6C^hi monocytic precursors. At the macrophage level, M-CSFR signaling blockade caused a shift in the MHC-II^lo/MHC-II^hi TAM balance in favor of the latter due to a preferential differentiation of Ly6C^hi monocytes towards MHC-II^hi TAM. In addition, M-CSFR signaling appeared to be crucial in shaping the MHC-II^lo TAM phenotype, since genes, proteins and functions associated with MHC-II^lo TAM were downregulated upon M-CSFR blockade. Conversely, GM-CSFR had no role in the recruitment or intratumoral differentiation of Ly6C^hi 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-II^hi 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.