Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor β

Nagai, Taku; Tanaka, Masashi; Tsuneyoshi, Yasuhiro; Xu, Baohui; Michie, Sara A.; Hasui, Kazuhisa; Hirano, Hirofumi; Arita, Kazunori; Matsuyama, Tomohiko

doi:10.1007/s00262-009-0667-x

Cited by 121 publications

(108 citation statements)

References 33 publications

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“…+ cells within human and rat glioblastoma (36). In an apparent contradiction, gene expression profiling has revealed downregulated FRβ mRNA levels in murine fibrosarcoma TAM relative to the levels detected in thioglycollate-elicited peritoneal macrophages (12).…”

Section: Resultsmentioning

confidence: 99%

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Folate Receptor β Is Expressed by Tumor-Associated Macrophages and Constitutes a Marker for M2 Anti-inflammatory/Regulatory Macrophages

et al. 2009

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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]

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Section: Resultsmentioning

confidence: 99%

“…+ murine peritoneal macrophages (36), where its mRNA levels can be further upregulated by IL-4 (37). Therefore, FRβ expression seems not to be restricted to anti-inflammatory/regulatory IL-10-producing M2 macrophages and marks a wider range of alternatively activated macrophages in the human and murine systems.…”

Section: Resultsmentioning

confidence: 99%

Folate Receptor β Is Expressed by Tumor-Associated Macrophages and Constitutes a Marker for M2 Anti-inflammatory/Regulatory Macrophages

et al. 2009

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“…3,4 Recently, gene silencing by small interfering RNA (siRNA) of different therapeutic targets has emerged as a promising new approach that is able to inhibit glioblastoma growth in vitro and ex vivo. [5][6][7][8] Because decreasing the number of tumorassociated macrophages leads to reduced tumor growth in vivo, 9 eliminating both glioblastoma cells and macrophages could result in a better therapeutic outcome.…”

Section: Introductionmentioning

confidence: 99%

Uptake and intracellular traffic of siRNA dendriplexes in glioblastoma cells and macrophages

Perez¹,

Cosaka²,

Romero³

et al. 2011

IJN

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Background: Gene silencing using small interfering RNA (siRNA) is a promising new therapeutic approach for glioblastoma. The endocytic uptake and delivery of siRNA to intra cellular compartments could be enhanced by complexation with polyamidoamine dendrimers. In the present work, the uptake mechanisms and intracellular traffic of siRNA/generation 7 dendrimer complexes (siRNA dendriplexes) were screened in T98G glioblastoma and J774 macrophages. Methods: The effect of a set of chemical inhibitors of endocytosis on the uptake and silenc ing capacity of dendriplexes was determined by flow cytometry. Colocalization of fluorescent dendriplexes with endocytic markers and occurrence of intracellular dissociation were assessed by confocal laser scanning microscopy. Results: Uptake of siRNA dendriplexes by T98G cells was reduced by methylβcyclodextrin, and genistein, and cytochalasine D, silencing activity was reduced by genistein; dendriplexes colocalized with cholera toxin subunit B. Therefore, caveolindependent endocytosis was involved both in the uptake and silencing activity of siRNA dendriplexes. On the other hand, uptake of siRNA dendriplexes by J774 cells was reduced by methylβcyclodextrin, genistein, chlorpromazine, chloroquine, cytochalasine D, and nocodazole, the silencing activity was not affected by chlorpromazine, genistein or chloroquine, and dendriplexes colocalized with transferrin and cholera toxin subunit B. Thus, both clathrindependent and caveolindependent endocytosis mediated the uptake and silencing activity of the siRNA dendriplexes. SiRNA dendriplexes were internalized at higher rates by T98G but induced lower silencing than in J774 cells. SiRNA dendriplexes showed relatively slow dissociation kinetics, and their escape towards the cytosol was not mediated by acidification independently of the uptake pathway. Conclusion: The extent of cellular uptake of siRNA dendriplexes was inversely related to their silencing activity. The higher silencing activity of siRNA dendriplexes in J774 cells could be ascribed to the contribution of clathrindependent and caveolindependent endocytosis vs only caveolindependent endocytosis in T98G cells.

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“…Therefore, TAMs are considered as potential target for anticancer therapy (4)(5)(6)(7). Tumor growth and metastasis can be suppressed by decreasing the number of TAMs in tumor (8)(9)(10). In contrast, Gr-1 + CD11b + F4/80 + cells in tumor-bearing mice have been defined as myeloid-derived suppressor cells (MDSCs), which inhibit antitumor T cell responses (11,12).…”

mentioning

confidence: 99%

Tumor Cell-Released TLR4 Ligands Stimulate Gr-1+CD11b+F4/80+ Cells to Induce Apoptosis of Activated T Cells

Liu

Sun²,

Wei³

et al. 2010

The Journal of Immunology

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Gr-1+CD11b+F4/80+ cells play important roles in tumor development and have a negative effect on tumor immunotherapy. So far, the mechanisms underlying the regulation of their immunosuppressive phenotype by classical and alternative macrophage activation stimuli are not well elucidated. In this study, we found that molecules from necrotic tumor cells (NTC-Ms) stimulated Gr-1+CD11b+F4/80+ cells to induce apoptosis of activated T cells but not nonstimulated T cells. The apoptosis-inducing capacity was determined by higher expression levels of arginase I and IL-10 relative to those of NO synthase 2 and IL-12 in Gr-1+CD11b+F4/80+ cells, which were induced by NTC-Ms through TLR4 signaling. The apoptosis-inducing capacity of NTC-Ms–stimulated Gr-1+CD11b+F4/80+ cells could be enhanced by IL-10. IFN-γ may reduce the apoptosis-inducing capacity of Gr-1+CD11b+F4/80+ cells only if their response to IFN-γ was not attenuated. However, the potential of Gr-1+CD11b+F4/80+ cells to express IL-12 in response to IFN-γ could be attenuated by tumor, partially due to the existence of active STAT3 in Gr-1+CD11b+F4/80+ cells and NTC-Ms from tumor. In this situation, IFN-γ could not effectively reduce the apoptosis-inducing capacity of Gr-1+CD11b+F4/80+ cells. Tumor immunotherapy with 4-1BBL/soluble programmed death-1 may significantly reduce, but not abolish the apoptosis-inducing capacity of Gr-1+CD11b+F4/80+ cells in local microenvironment. Blockade of TLR4 signaling could further reduce the apoptosis-inducing capacity of Gr-1+CD11b+F4/80+ cells and enhance the suppressive effect of 4-1BBL/soluble form of programmed death-1 on tumor growth. These findings indicate the relationship of distinct signaling pathways with apoptosis-inducing capacity of Gr-1+CD11b+F4/80+ cells and emphasize the importance of blocking TLR4 signaling to prevent the induction of T cell apoptosis by Gr-1+CD11b+F4/80+ cells.

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Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor β

Cited by 121 publications

References 33 publications

Folate Receptor β Is Expressed by Tumor-Associated Macrophages and Constitutes a Marker for M2 Anti-inflammatory/Regulatory Macrophages

Folate Receptor β Is Expressed by Tumor-Associated Macrophages and Constitutes a Marker for M2 Anti-inflammatory/Regulatory Macrophages

Uptake and intracellular traffic of siRNA dendriplexes in glioblastoma cells and macrophages

Tumor Cell-Released TLR4 Ligands Stimulate Gr-1+CD11b+F4/80+ Cells to Induce Apoptosis of Activated T Cells

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