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  • Review Article
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The polarization of immune cells in the tumour environment by TGFβ

Nature Reviews Immunology volume 10, pages 554–567 (2010)Cite this article

Subjects

Key Points

  • During early tumour formation, transforming growth factor-β (TGFβ) can function as a tumour suppressor to prevent tumorigenesis; however, overproduction of TGFβ in established tumours is often associated with tumour metastasis and poor prognosis in patients with cancer.

  • The tumour-promoting effects of TGFβ may be due to the immunosuppressive effects it has on both innate and adaptive immunity.

  • TGFβ inhibits natural killer cell function by inhibiting cytokine production and downregulating the expression of activating receptors.

  • TGFβ inhibits the maturation of, and cytokine production and proper antigen presentation by, dendritic cells, while promoting regulatory T (TReg) cell differentiation and an overall tolerogenic state. TGFβ also promotes an M2 phenotype for macrophages and an N2 phenotype for neutrophils.

  • TGFβ directly dampens the function of CD4+ and CD8+ effector T cells and promotes the survival of TReg cells. Depending on the cytokine milieu, TGFβ greatly affects the differentiation of several key CD4+ T cell subsets in tumour immunology.

  • There is great interest in targeting TGFβ-induced signalling for immunotherapy of cancer; however, the dosing, timing and combination of this approach with other immunotherapies to achieve the most successful antitumour effect need to be further investigated.

Abstract

Transforming growth factor-β (TGFβ) 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 TGFβ 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 TGFβ-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 TGFβ-induced signalling and their phase in clinical development is also provided.

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Figure 1: The yin and yang of TGFβ in tumour development, maintenance and metastasis formation.
Figure 2: Effects of TGFβ on innate immune cells.
Figure 3: Effects of TGFβ on effector T cells.
Figure 4: Effects of TGFβ on regulatory T cells.
Figure 5: Targets for inhibiting TGFβ and downstream signalling events.

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Acknowledgements

R.A.F. is an investigator of the Howard Hughes Medical Institute. This work is supported by a post-doctoral fellowship grant from the Cancer Research Institute (to S.S.), the NCI-funded Yale SPORE in Skin Cancer (P50 CA121974) through a Yale Skin SPORE Career Development Award (to S.H.W.) and a post-doctoral fellowship from PEW Charitable Trust: PEW Latin American Fellow Program in Biomedical Sciences (to P.L-L.). Additional support from NIH grants CA121974 and DK051665 (to R.A.F.) and JDRF grant 32-2008-352 (to R.A.F.).

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  1. Shomyseh Sanjabi

    Present address: Present address: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA, and Department of Microbiology and Immunology, University of California, San Francisco, California 94143-1230, USA.,

  2. Stephen H. Wrzesinski

    Present address: Present address: Veteran's Administration Connecticut Health Care System and Comprehensive Cancer Center, 950 Campbell Avenue, West Haven, Connecticut 06516, USA.,

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  1. Yale University School of Medicine, 300 Cedar Street, TAC S-569, PO BOX 208011, New Haven, 06520, Connecticut, USA

    Richard A. Flavell, Shomyseh Sanjabi, Stephen H. Wrzesinski & Paula Licona-Limón

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Glossary

Peripheral tolerance

The lack of responsiveness of mature lymphocytes in the periphery to specific self antigens. These mechanisms can control potentially self-reactive lymphocytes that have escaped central tolerance or prevent immune responses to specialized self proteins that were not present during establishment of central tolerance. Peripheral tolerance is associated with suppression of self-reactive antibody production by B cells and inhibition of self-reactive effector cells, such as T helper cells and cytotoxic T lymphocytes.

Myeloid-derived suppressor cells

(MDSCs). A subset of immature CD11b+GR1+ cells (which include precursors of macrophages, granulocytes, dendritic cells and myeloid cells) that are produced in response to various tumour-derived cytokines. These cells have been shown to induce tumour-associated antigen-specific CD8+ T cell tolerance.

Tumour-associated macrophages

(TAMs). An important component of the tumour microenvironment. These cells differentiate from circulating blood monocytes that have infiltrated tumours. They can have positive or negative effects on tumorigenesis (that is, tumour promotion or immunosurveillance, respectively).

M1 macrophage

A classically activated macrophage that is stimulated by Toll-like receptor ligands (such as lipopolysaccharide) and IFNγ and that expresses, among others, inducible nitric-oxide synthase and nitric oxide.

M2 macrophage

An alternatively activated macrophage that is stimulated by IL-4 or IL-13 and that expresses arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain.

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Flavell, R., Sanjabi, S., Wrzesinski, S. et al. The polarization of immune cells in the tumour environment by TGFβ. Nat Rev Immunol 10, 554–567 (2010). https://doi.org/10.1038/nri2808

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