The polarization of immune cells in the tumour environment by TGF&UF062. Nat Rev Immunol

Yale University School of Medicine, 300 Cedar Street, TAC S-569, PO BOX 208011, New Haven, Connecticut 06520, USA.
Nature Reviews Immunology (Impact Factor: 34.99). 08/2010; 10(8):554-67. DOI: 10.1038/nri2808
Source: PubMed


Transforming growth factor-beta (TGFbeta) is an immunosuppressive cytokine produced by tumour cells and immune cells that can polarize many components of the immune system. This Review covers the effects of TGFbeta on natural killer (NK) cells, dendritic cells, macrophages, neutrophils, CD8(+) and CD4(+) effector and regulatory T cells, and NKT cells in animal tumour models and in patients with cancer. Collectively, many recent studies favour the hypothesis that blocking TGFbeta-induced signalling in the tumour microenvironment enhances antitumour immunity and may be beneficial for cancer therapy. An overview of the current drugs and reagents available for inhibiting TGFbeta-induced signalling and their phase in clinical development is also provided.

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Available from: Richard A Flavell
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    • "In mice models, macrophages present CD11b, F4/80, and colony-stimulating factor-1 receptor (CSF-1R), with F4/80 being the surface proteins for M1 and M2 macrophages [11] [20]. TAMs have the major role in the tumor microenvironment to bear immune inhibitory effect [20] [21]. Tumor cells and the surrounding stoma cells secrete cytokines and growth factors that stimulate TAMs and activate the various expressions, functions, receptor regulations, and secretions of chemokines [22] [23], including antitumor M1 macrophages and protumor M2 macrophages [16, 24–26]. "
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    ABSTRACT: The present study showed that oral mushroom beta-glucan treatment significantly increased IFN-γ mRNA expression but significantly reduced COX-2 mRNA expression within the lung. For LLC tumor model, oral Ganoderma lucidum or Antrodia camphorata polysaccharides treatments significantly reduced TGF-β production in serum. In addition, IL-12 and IFN-γ mRNA expression were significantly increased, but IL-6, IL-10, COX-2, and TGF-β mRNA expression were substantially following oral mushroom polysaccharides treatments. The study highlights the efficacious effect of mushroom polysaccharides for ameliorating the immune suppression in the tumor microenvironment. Increased M1 phenotype of tumor-associated macrophages and attenuated M2 phenotype of tumor-associated macrophages could be achieved by ingesting mushroom polysaccharides.
    Full-text · Article · Jul 2015
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    • "Understanding what is truly relevant for the abrogation of protective immunity in different cancers is needed for implementing more effective antitumor immunotherapies. Transforming growth factor-b (TGF-b) is a lymphocyte inhibitor secreted by multiple cells and frequently overexpressed in aggressive cancers (Flavell et al., 2010; Wrzesinski et al., 2007). Tumors induce dendritic cells (DCs) to secrete TGF-b, promoting regulatory T cell (Treg) expansion and indirect suppression of T cell effectors (Ghiringhelli et al., 2005; Hanks et al., 2013). "
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    ABSTRACT: Tumor-reactive T cells become unresponsive in advanced tumors. Here we have characterized a common mechanism of T cell unresponsiveness in cancer driven by the upregulation of the transcription factor Forkhead box protein P1 (Foxp1), which prevents CD8(+) T cells from proliferating and upregulating Granzyme-B and interferon-γ in response to tumor antigens. Accordingly, Foxp1-deficient lymphocytes induced rejection of incurable tumors and promoted protection against tumor rechallenge. Mechanistically, Foxp1 interacted with the transcription factors Smad2 and Smad3 in preactivated CD8(+) T cells in response to microenvironmental transforming growth factor-β (TGF-β), and was essential for its suppressive activity. Therefore, Smad2 and Smad3-mediated c-Myc repression requires Foxp1 expression in T cells. Furthermore, Foxp1 directly mediated TGF-β-induced c-Jun transcriptional repression, which abrogated T cell activity. Our results unveil a fundamental mechanism of T cell unresponsiveness different from anergy or exhaustion, driven by TGF-β signaling on tumor-associated lymphocytes undergoing Foxp1-dependent transcriptional regulation.
    Full-text · Article · Sep 2014 · Immunity
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    • "We also observed a decrease in mRNA encoding the immunosuppressive cytokine TGFβ in mice treated with CpG ODN plus 3M-052. TGFβ is produced by tumor cells and Gr-1+ CD11b+ MDSC in the tumor microenvironment and serves to suppress both innate and adaptive arms of the immune system [29,46,47]. Consistent with current findings, reduced TGFβ signaling is known to enhance tumor elimination by improving CTL activity [32,33]. "
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    ABSTRACT: Background The TLR7/8 agonist 3M-052 and the TLR9 agonist CpG ODN both trigger innate immune responses that support the induction of tumor-specific immunity. Previous studies showed that these agonists used individually could improve the survival of mice challenged with small tumors but were of limited therapeutic benefit against large/advanced tumors. Methods Normal mice were challenged with syngeneic tumors. Once these tumors reached clinically detectable size (500–800 mm3) they were treated by intra-tumoral injection with 3M-052 and/or CpG ODN. Anti-tumor immunity and tumor growth were evaluated. Results The co-delivery of agonists targeting TLRs 7, 8 and 9 increased the number and tumoricidal activity of tumor infiltrating CTL and NK cells while reducing the frequency of immunosuppressive MDSC. The combination of 3M-052 plus CpG ODN (but not each agent alone) eradicated large primary tumors and established long-term protective immunity. Conclusion The combination of agonists targeting TLRs 7/8 and 9 represents a significant improvement in cancer immunotherapy.
    Full-text · Article · May 2014
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