Trends in Immunology
ReviewTGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression
Section snippets
TGF-β signaling, a tumor suppressor and a tumor promoter
Transforming growth factor β (TGF-β) signaling plays a very important role in tumor initiation and progression 1, 2. There are three TGF-β ligands, TGF-β1, TGF-β2 and TGF-β3. TGF-β1 is the most commonly upregulated in tumor cells [3]. The TGF-β ligands signal through type I and type II TGF-β receptors (TβRI and TβRII, respectively). Upon binding of TGF-β to TβRII, TβRI is recruited, transphosphorylated and activated to phosphorylate the downstream mediators, SMAD2 and SMAD3. Phosphorylated
Challenges in understanding the dual role of TGF-β
The mechanisms underlying the dual role of TGF-β described above are very complex and intricate 2, 17, 18. Tumor progression from premalignant to metastatic disease is generally accompanied by decreased or altered TGF-β responsiveness and increased expression or activation of the TGF-β ligand. When combined with genetic or epigenetic perturbations in tumor cells, along with alteration in the tumor microenvironment, the spectrum of biological responses to TGF-β is altered (Figure 2). In the
Effect of TGF-β on systemic immune surveillance of tumor host
TGF-β controls immune responses and maintains immune homeostasis through its impact on proliferation, differentiation and survival of multiple immune cell lineages 23, 24, 25. TGF-β has an adverse effect on anti-tumor immunity and inhibits significantly host tumor immune surveillance 23, 26. The effect of TGF-β on T cells was demonstrated clearly by genetic deletion or attenuation of TGF-β signaling. Transgenic mice with a dominant-negative Tgfbr2 under a T-cell-specific promoter showed
TGF-β regulation of the tumor microenvironment
The tumor microenvironment is filled with various inflammatory cells, including myeloid cell subpopulations, innate and adaptive immune cells NK(T) cells, T cells and B cells (Figure 4a). In addition, there is an abundance of cancer-associated fibroblasts (CAFs) and endothelial progenitor cells (EPCs) [64] (Figure 4a). This very dynamic tumor microenvironment probably serves as a selective pressure for tumor cell variants through genomic instability, genomic heterogeneity and epigenetic
Antitumor activity of TGF-β inhibition is dependent on the host immune and inflammatory response: implications for therapy
TGF-β has been identified as a therapeutic target because of its significant tumor- promoting roles. Approaches include a variety of neutralizing antibodies and small molecular inhibitors. However, the goal of these therapies is to abolish the tumor- promoting effect of TGF-β, while maintaining its tumor suppressive properties. Recent developments in the field point out that the efficacy of TGF-β antagonist therapy might not derive from a direct effect on tumor cells as was originally thought.
References (86)
TGFbeta in Cancer
Cell
(2008)The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling
Cell
(1997)- et al.
TGF-beta signaling in cancer–a double-edged sword
Trends Cell Biol.
(2001) Loss of TGFbeta signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia
Cancer Cell
(2007)High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene
Cancer Cell
(2007)Inhibition of TGFbeta signaling in cancer therapy
Curr. Opin. Genet. Dev.
(2006)TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4
Cell
(2008)A mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis
Cell
(2009)FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination
Cell
(2009)- et al.
TGF-beta: a master of all T cell trades
Cell
(2008)
TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance
Cancer Cell
The dual adverse effects of TGF-beta secretion on tumor progression
Cancer Cell
Mechanisms of foxp3+ T regulatory cell-mediated suppression
Immunity
TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells
Immunity
TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo
Immunity
The ‘short’ history of regulatory B cells
Trends Immunol.
A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses
Immunity
De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent
Cancer Cell
Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T-cell suppressive activity
Blood
Abrogation of TGFbeta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis
Cancer Cell
Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis
Cancer Cell
Macrophages: obligate partners for tumor cell migration, invasion, and metastasis
Cell
A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kB and enhanced IRF-3/STAT1 activation)
Blood
Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN
Cancer Cell
The yin-yang of tumor-associated neutrophils
Cancer Cell
HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion
Cancer Cell
A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gut inflammation
J. Biol. Chem.
Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment
Cancer Cell
Tumour microenvironment : TGFβ: the molecular Jekyll and Hyde of cancer
Nat. Rev. Cancer
Smad-dependent and Smad-independent pathways in TGF-beta family signalling
Nature
Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling
Nature
Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability
Science
Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study
Cancer Res.
Transforming growth factor beta: tumor suppressor or promoter? Are host immune cells the answer?
Cancer Res.
Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumor development in mice
Mol. Cell Biol.
Molecular predictors of survival after adjuvant chemotherapy for colon cancer
N. Engl. J. Med.
Metastasis to bone: causes, consequences and therapeutic opportunities
Nat. Rev. Cancer
Transforming growth factor-beta in osteolytic breast cancer bone metastases
Clin. Orthop. Relat. Res.
The two faces of transforming growth factor beta in carcinogenesis
Proc. Natl. Acad. Sci. U. S. A.
Gain or loss of TGFbeta signaling in mammary carcinoma cells can promote metastasis
Cell Cycle
TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch
EMBO J.
Transforming growth factor-beta regulation of immune responses
Annu. Rev. Immunol.
Transforming growth factor-beta in T-cell biology
Nat. Rev. Immunol.
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