M-CSF and GM-CSF Receptor Signaling Differentially Regulate Monocyte Maturation and Macrophage Polarization in the Tumor Microenvironment
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M-CSF and GM-CSF Receptor Signaling Differentially Regulate Monocyte Maturation and Macrophage Polarization in the Tumor Microenvironment. / Van Overmeire, Eva; Stijlemans, Benoît; Heymann, Felix; Keirsse, Jiri; Morias, Yannick; Elkrim, Yvon; Brys, Lea; Abels, Chloé; Lahmar, Qods; Ergen, Can; Vereecke, Lars; Tacke, Frank; De Baetselier, Patrick; Van Ginderachter, Jo A; Laoui, Damya.
in: CANCER RES, Jahrgang 76, Nr. 1, 01.01.2016, S. 35-42.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - M-CSF and GM-CSF Receptor Signaling Differentially Regulate Monocyte Maturation and Macrophage Polarization in the Tumor Microenvironment
AU - Van Overmeire, Eva
AU - Stijlemans, Benoît
AU - Heymann, Felix
AU - Keirsse, Jiri
AU - Morias, Yannick
AU - Elkrim, Yvon
AU - Brys, Lea
AU - Abels, Chloé
AU - Lahmar, Qods
AU - Ergen, Can
AU - Vereecke, Lars
AU - Tacke, Frank
AU - De Baetselier, Patrick
AU - Van Ginderachter, Jo A
AU - Laoui, Damya
N1 - ©2015 American Association for Cancer Research.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
KW - Animals
KW - Antibodies, Monoclonal
KW - Carcinoma, Lewis Lung
KW - Cell Differentiation
KW - Cell Polarity
KW - Female
KW - Macrophage Colony-Stimulating Factor
KW - Macrophages
KW - Mammary Neoplasms, Experimental
KW - Mice
KW - Mice, Inbred C57BL
KW - Monocytes
KW - Receptors, Colony-Stimulating Factor
KW - Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
KW - Signal Transduction
KW - Tumor Microenvironment
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1158/0008-5472.CAN-15-0869
DO - 10.1158/0008-5472.CAN-15-0869
M3 - SCORING: Journal article
C2 - 26573801
VL - 76
SP - 35
EP - 42
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 1
ER -