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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / immunology
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / pathology
  • Cell Differentiation / physiology
  • Cell Polarity / physiology
  • Female
  • Macrophage Colony-Stimulating Factor / immunology
  • Macrophage Colony-Stimulating Factor / metabolism
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / metabolism*
  • Monocytes / pathology
  • Receptors, Colony-Stimulating Factor / antagonists & inhibitors
  • Receptors, Colony-Stimulating Factor / immunology
  • Receptors, Colony-Stimulating Factor / metabolism*
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Signal Transduction
  • Tumor Microenvironment / physiology*


  • Antibodies, Monoclonal
  • Receptors, Colony-Stimulating Factor
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Macrophage Colony-Stimulating Factor