Folate Receptor β Is Expressed by Tumor-Associated Macrophages and Constitutes a Marker for M2 Anti-inflammatory/Regulatory Macrophages
Top Cited Papers
Open Access
- 14 December 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 69 (24), 9395-9403
- https://doi.org/10.1158/0008-5472.can-09-2050
Abstract
Macrophage activation comprises a continuum of functional states critically determined by cytokine microenvironment. Activated macrophages have been functionally grouped according to their response to pro-Th1/proinflammatory stimuli [lipopolysaccharide, IFNγ, granulocyte macrophage colony-stimulating factor (GM-CSF); M1] or pro-Th2/anti-inflammatory stimuli [interleukin (IL)-4, IL-10, M-CSF; M2]. We report that folate receptor β (FRβ), encoded by the FOLR2 gene, is a marker for macrophages generated in the presence of M-CSF (M2), but not GM-CSF (M1), and whose expression correlates with increased folate uptake ability. The acquisition of folate uptake ability by macrophages is promoted by M-CSF, maintained by IL-4, prevented by GM-CSF, and reduced by IFNγ, indicating a link between FRβ expression and M2 polarization. In agreement with in vitro data, FRβ expression is detected in tumor-associated macrophages (TAM), which exhibit an M2-like functional profile and exert potent immunosuppressive functions within the tumor environment. FRβ is expressed, and mediates folate uptake, by CD163+ CD68+ CD14+ IL-10–producing TAM, and its expression is induced by tumor-derived ascitic fluid and conditioned medium from fibroblasts and tumor cell lines in an M-CSF–dependent manner. These results establish FRβ as a marker for M2 regulatory macrophage polarization and indicate that folate conjugates of therapeutic drugs are a potential immunotherapy tool to target TAM. [Cancer Res 2009;69(24):9395–403]Keywords
Other Versions
This publication has 42 references indexed in Scilit:
- Trophic macrophages in development and diseaseNature Reviews Immunology, 2009
- A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophagesBlood, 2009
- Gene Expression Profiling of Human Decidual Macrophages: Evidence for Immunosuppressive PhenotypePLOS ONE, 2008
- Human peritoneal macrophages show functional characteristics of M‐CSF‐driven anti‐inflammatory type 2 macrophagesEuropean Journal of Immunology, 2007
- Role of tumor-associated macrophages in tumor progression and invasionCancer and Metastasis Reviews, 2006
- Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and MetastasisCell, 2006
- Monocyte and macrophage heterogeneityNature Reviews Immunology, 2005
- Mechanisms and functional significance of tumour-induced dendritic-cell defectsNature Reviews Immunology, 2004
- Tumour-educated macrophages promote tumour progression and metastasisNature Reviews Cancer, 2004
- Alternative activation of macrophagesNature Reviews Immunology, 2003