Folate receptor beta is expressed by tumor-associated macrophages and constitutes a marker for M2 anti-inflammatory/regulatory macrophages.
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.
Puig-Kröger
Amaya
A
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Hospital General Universitario Gregorio Marañón, Madrid, Spain. apuig.hgugm@salud.madrid.org
Sierra-Filardi
Elena
E
Domínguez-Soto
Angeles
A
Samaniego
Rafael
R
Corcuera
María Teresa
MT
Gómez-Aguado
Fernando
F
Ratnam
Manohar
M
Sánchez-Mateos
Paloma
P
Corbí
Angel L
AL
D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D058973:Folate Receptors, GPI-Anchored; D020869:Gene Expression Profiling; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D016173:Macrophage Colony-Stimulating Factor