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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-12, Vol.69 (24), p.9395-9403
• Main Authors: Puig-Kröger, Amaya, Sierra-Filardi, Elena, Domínguez-Soto, Angeles, Samaniego, Rafael, Corcuera, María Teresa, Gómez-Aguado, Fernando, Ratnam, Manohar, Sánchez-Mateos, Paloma, Corbí, Angel L
• Format: Article
• Language: English
• Subjects: Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Cell Line, Tumor; Folate Receptors, GPI-Anchored; Gene Expression Profiling; Humans; Macrophage Colony-Stimulating Factor - pharmacology; Macrophages - immunology; Melanoma - immunology; Receptors, Cell Surface - biosynthesis; Receptors, Cell Surface - genetics; RNA, Messenger - biosynthesis; RNA, Messenger - genetics
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-2050

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.