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

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, IFNgamma, 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 beta (FRbeta), 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 IFNgamma, indicating a link between FRbeta expression and M2 polarization. In agreement with in vitro data, FRbeta expression is detected in tumor-associated macrophages (TAM), which exhibit an M2-like functional profile and exert potent immunosuppressive functions within the tumor environment. FRbeta 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 FRbeta as a marker for M2 regulatory macrophage polarization and indicate that folate conjugates of therapeutic drugs are a potential immunotherapy tool to target TAM.

• Authors: Amaya Puig-Kröger, Elena Sierra-Filardi, Angeles Domínguez-Soto, Rafael Samaniego, María Teresa Corcuera, Fernando Gómez-Aguado, Manohar Ratnam, Paloma Sánchez-Mateos, Angel L Corbí
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 24 Pg. 9395-403 (Dec 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19951991 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Folate Receptors, GPI-Anchored
• RNA, Messenger
• Receptors, Cell Surface
• Macrophage Colony-Stimulating Factor

Topics

• Carrier Proteins (biosynthesis, genetics)
• Cell Line, Tumor
• Folate Receptors, GPI-Anchored
• Gene Expression Profiling
• Humans
• Macrophage Colony-Stimulating Factor (pharmacology)
• Macrophages (immunology)
• Melanoma (immunology)
• RNA, Messenger (biosynthesis, genetics)
• Receptors, Cell Surface (biosynthesis, genetics)