Inhibition of TGF-β signaling in combination with TLR7 ligation re-programs a tumoricidal phenotype in tumor-associated macrophages

Jiao, Peng; Tsang, Julia Yuen Shan; Li, Daxu; Niu, Na; Ho, Derek Hoi Hang; Lau, Kwok‐Fai; Lui, Vincent Chi Hang; Lamb, Jonathan R.; Chen, Yan; Tam, Paul Kwong Hang

doi:10.1016/j.canlet.2013.01.001

Cited by 50 publications

(32 citation statements)

References 34 publications

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“…Supportingly, results of luciferase assays showed that TGF-β enhanced the Tim-3 promoter activities (figure 5D). Considering the active involvement of macrophages in many TGF-β-related diseases,30 31 our data here highlight the potential role of Tim-3 in multiple pathological conditions by regulating macrophage functions.…”

Section: Discussionmentioning

confidence: 58%

Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages

Yan

Liu

Hong

et al. 2015

Gut

273

243

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Section: Discussionmentioning

confidence: 58%

Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages

Yan

Liu

Hong

et al. 2015

Gut

273

243

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“…1D). Furthermore, NFSA-CM induced much higher expression of CD80, the well-established M1-macrophage marker (18), in RAW264 cells than did MS-K-CM (Fig. 1E).…”

Section: Resultsmentioning

confidence: 94%

Enhancement of phagocytosis and cytotoxicity in macrophages by tumor-derived IL-18 stimulation

et al. 2014

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Inoculation of mice with the murine NFSA cell line caused the formation of large tumors with necrotic tumor cores. FACS analysis revealed accumulations of CD11b+ cells in the tumors. Microarray analysis indicated that the NFSA cells expressed a high level of the pro-inflammatory factor interleukin-18 (il-18), which is known to play a critical role in macrophages. However, little is known about the physiological function of IL-18-stimulated macrophages. Here, we provide direct evidence that IL-18 enhances the phagocytosis of RAW264 cells and peritoneal macrophages, accompanied by the increased expression of tumor necrosis factor (tnf-α), interleukin-6 (il-6) and inducible nitric oxide synthase (Nos2). IL-18-stimulated RAW264 cells showed an enhanced cytotoxicity to endothelial F-2 cells via direct cell-to-cell interaction and the secretion of soluble mediators. Taken together, our results demonstrate that tumor-derived IL-18 plays an important role in the phagocytosis of macrophages and that IL-18-stimulated macrophages may damage tumor endothelial cells. [BMB Reports 2014; 47(5): 286-291]

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“…But generally, results with anti-TGF-β antibodies have been disappointing to date, and TGF-β-neutralizing antibodies may have adverse effects in normal healthy tissues. Ligation of Toll-like receptor 7, which is expressed on TAMs, but not tumor cells, in the presence of TGF-βRI inhibitor, reprogrammed the phenotype of the TAMs to M1-type with increased tumoricidal activity and elevated expression of iNOS, CD80, and MHC class II, whereas TGF-β secretion was reduced ( 11 ). This combination also increased tumor apoptosis and elevated the number of CD4 + , CD8 + , and CD19…”

Section: Cd4mentioning

confidence: 89%

Myeloid TGF-β Responsiveness Promotes Metastases

Souza-Fonseca-Guimarães¹,

Smyth²

2013

Cancer Discovery

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Summary : Tumor-induced immune suppression is a major impediment to many potentially effective cancer therapies. TGF-β has previously been described as having both tumor-promoting and tumor-suppressive characteristics. In this issue of Cancer Discovery , Pang and colleagues show that myeloid-specifi c TGF-β signaling is a critical mediator in tumor metastasis. These fi ndings point to a more specifi c means to reduce cancer immunosuppression, prevent metastasis, and minimize treatment-related adverse events. Cancer Discov; 3(8); ©2013 AACR.See related article by Pang et al., p. 936 (3).Immune evasion represents one of the most contemporary hallmarks of cancer, and myeloid cells are one of the most important cell types in the suppression of host immune surveillance, consequent tumor progression ( 1 ), and premetastatic niche formation ( 2 ). These tumor-infi ltrating myeloid cells include tumor-associated macrophages (TAM, CD11b CD11b+ myeloid-derived suppressor cells that can be divided into myeloid monocytes (CD11b. All of these cell types potentially produce TGF-β within the tumor microenvironment. TGF-β is also overexpressed in advanced human cancers, and its expression correlates with metastasis and poor prognosis. In addition to the fact that many cell types can both produce and respond to TGF-β, another great challenge in our understanding of TGF-β cancer biology and the successful application of TGF-β-targeted therapy is that TGF-β works as both a tumor suppressor and a tumor promoter.Consequently, there has been a great need to understand which TGF-β-sensitive cell type is the most important in tumor promotion and spread. Now, Pang and colleagues ( 3 ) report that genetic deletion of TGF-β type II receptor ( Tgfbr2 ) specifi cally in mouse myeloid cells using the LysM-cre strain ( Tgfbr2 MyeKO ) signifi cantly inhibited tumor metastasis. Importantly, the Tgfbr2MyeKO mice had no alteration in the number or percentage of T, B, NK, or Gr1+ and F4/80 + cells. Reconstitution of tumor-bearing mice with Tgfbr2MyeKO bone marrow recapitulated the reduced metastasis phenotype. Reduced metastasis was mediated through decreased production of type II cytokines, TGF-β1, arginase 1, and iNOS, which promoted IFN-γ production and improved systemic CD8 + T-cell systemic immunity in the Tgfbr2MyeKO mice (Fig. 1) . This work follows on from other intensive efforts in this area. In particular, by crossing LysM-Cre and Tgfbr2 fl oxed mice, Novitskiy and colleagues ( 4 ) also achieved specifi c deletion of Tgfbr2 in myeloid cells in the C57BL/6 strain background. In contrast to Pang and colleagues ( 3 ), where no, or only modest, effects on orthotopic tumor growth were noted, Novitskiy and colleagues ( 4 ) showed the slower growth of a variety of subcutaneously transplanted syngeneic tumors in Tgfbr2MyeKO mice. They also reported an increase in the percentage of T cells (CD3 + ) in the primary tumors in Tgfbr2MyeKO mice, but no change in the myeloid cell infi ltrates. The dendritic cells from tumor tissue of Tgfbr2MyeKO mice...

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Inhibition of TGF-β signaling in combination with TLR7 ligation re-programs a tumoricidal phenotype in tumor-associated macrophages

Cited by 50 publications

References 34 publications

Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages

Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages

Enhancement of phagocytosis and cytotoxicity in macrophages by tumor-derived IL-18 stimulation

Myeloid TGF-β Responsiveness Promotes Metastases

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