Background. Despite significant differences in ligand binding between the two known isoforms of the human membrane folate receptor (FR), designated herein as FR β (placenta) and FR‐α (placenta, KB cells), little is known about their tissue specificities, and there is no report on the relative expression of FR‐β in any tissue other than in placenta. Methods. The mRNA for each FR isoform in a wide variety of normal fetal and adult tissue explants, primary normal cell cultures, malignant tumor explants, and established tumor cell lines was estimated by a polymerase chain reaction assay. Total receptor levels were estimated by a [3H] folic acid binding assay. Results. Both the FR isoforms were expressed in fetal as well as adult tissues. Normal tissues generally expressed low to moderate amounts of FR‐β. FR‐α alone was expressed in normal epithelial cells and was frequently strikingly elevated in a variety of carcinomas, with the exception of squamous cell carcinomas of the head and neck. In contrast, a variety of malignant tissues of nonepithelial origin generally expressed elevated levels of FR‐β alone. Established tumor cell lines expressed FR‐α virtually alone and did not reflect FR expression patterns in vivo. KB cells and JEG‐3 cells grown at low folate concentrations further up‐regulated FR‐α but not FR‐β. Conclusions. Although FR‐β is the more common isoform, FR‐α and FR‐β are differentially regulated in normal tissues, carcinomas, nonepithelial malignancies, and immortalized cells or in response to changes in extracellular folate concentrations. The tissue specificity of FR isoforms and their elevation in malignant tissues may be a significant factor in FR‐mediated folate uptake, in tissue responsiveness to promising novel antifolates, and in FR‐related immunodiagnosis/immunotherapy.

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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/antiinflammatory 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 tumorderived 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]