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

Abstract

<div>Abstract<p>Tumors contain a heterogeneous myeloid fraction comprised of discrete MHC-II<sup>hi</sup> and MHC-II<sup>lo</sup> tumor-associated macrophage (TAM) subpopulations that originate from Ly6C<sup>hi</sup> 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<sup>hi</sup> monocytic precursors. M-CSFR signaling blockade shifted the MHC-II<sup>lo</sup>/MHC-II<sup>hi</sup> TAM balance in favor of the latter as observed by the preferential differentiation of Ly6C<sup>hi</sup> monocytes into MHC-II<sup>hi</sup> TAMs. In addition, the genetic and functional signatures of MHC-II<sup>lo</sup> TAMs were downregulated upon M-CSFR blockade, indicating that M-CSFR signaling shapes the MHC-II<sup>lo</sup> 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<sup>hi</sup> 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. <i>Cancer Res; 76(1); 35–42. ©2015 AACR</i>.</p></div>