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Title

Folate receptor β is expressed by tumor-associated macrophages and constitutes a marker for M2 anti-inflammatory/regulatory Macrophages

AuthorsPuig-Kröger, Amaya ; Sierra-Filardi, Elena ; Domínguez-Soto, Ángeles ; Samaniego, Rafael ; Corcuera, María Teresa; Gómez-Aguado, Fernando; Ratnam, Manohar; Sánchez-Mateos, Paloma; Corbí, Angel L.
Issue Date2009
PublisherAmerican Association for Cancer Research
CitationCancer Research 69(24):9395-9403(2009)
AbstractMacrophage 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.
URIhttp://hdl.handle.net/10261/78386
DOI10.1158/0008-5472.CAN-09-2050
Identifiersdoi: 10.1158/0008-5472.CAN-09-2050
issn: 0008-5472
e-issn: 1538-7445
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