Trends in Immunology
Volume 31, Issue 6, June 2010, Pages 220-227
Journal home page for Trends in Immunology

Review
TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression

https://doi.org/10.1016/j.it.2010.04.002Get rights and content

Transforming growth factor β (TGF-β) plays an important role in tumor initiation and progression, functioning as both a suppressor and a promoter. The mechanisms underlying this dual role of TGF-β remain unclear. TGF-β exerts systemic immune suppression and inhibits host immunosurveillance. Neutralizing TGF-β enhances CD8+ T-cell- and NK-cell-mediated anti-tumor immune responses. It also increases neutrophil-attracting chemokines resulting in recruitment and activation of neutrophils with an antitumor phenotype. In addition to its systemic effects, TGF-β regulates infiltration of inflammatory/immune cells and cancer-associated fibroblasts in the tumor microenvironment causing direct changes in tumor cells. Understanding TGF-β regulation at the interface of tumor and host immunity should provide insights into developing effective TGF-β antagonists and biomarkers for patient selection and efficacy of TGF-β antagonist treatment.

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.

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