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Overcoming TGFβ-mediated immune evasion in cancer

Abstract

Transforming growth factor-β (TGFβ) signalling controls multiple cell fate decisions during development and tissue homeostasis; hence, dysregulation of this pathway can drive several diseases, including cancer. Here we discuss the influence that TGFβ exerts on the composition and behaviour of different cell populations present in the tumour immune microenvironment, and the context-dependent functions of this cytokine in suppressing or promoting cancer. During homeostasis, TGFβ controls inflammatory responses triggered by exposure to the outside milieu in barrier tissues. Lack of TGFβ exacerbates inflammation, leading to tissue damage and cellular transformation. In contrast, as tumours progress, they leverage TGFβ to drive an unrestrained wound-healing programme in cancer-associated fibroblasts, as well as to suppress the adaptive immune system and the innate immune system. In consonance with this key role in reprogramming the tumour microenvironment, emerging data demonstrate that TGFβ-inhibitory therapies can restore cancer immunity. Indeed, this approach can synergize with other immunotherapies — including immune checkpoint blockade — to unleash robust antitumour immune responses in preclinical cancer models. Despite initial challenges in clinical translation, these findings have sparked the development of multiple therapeutic strategies that inhibit the TGFβ pathway, many of which are currently in clinical evaluation.

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Fig. 1: TGFβ functions in healthy tissues and during cancer progression.
Fig. 2: TGFβ production, release and signalling.
Fig. 3: Regulation of stromal cell types by TGFβ in advanced cancer.

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Acknowledgements

D.V.F.T. is funded by a Hypatia Tenure Track Fellowship grant from Radboudumc and by the Dutch Research Council (NWO–ZonMw VIDI programme, grant number 91719371). E.B. receives support from the ERC (Advanced Grant 884623), World Wide Cancer Research grant (19_0005), “la Caixa” Foundation (HR18-00359), Government of Catalonia (AGAUR-SGR698) and Spanish Association Against Cancer (AECC PROYE18046BATL).

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All authors researched data for the article, wrote the article and reviewed and/or edited the manuscript before submission. E.B. and D.V.F.T. contributed substantially to discussion of the content.

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Correspondence to Daniele V. F. Tauriello or Eduard Batlle.

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E.B.’s research is sponsored by Incyte. E.B. and D.V.F.T. are authors named on the patent WO/2020/104648. E.S. and E.B. are authors named on the patents WO/2014/072517; WO/2021/063970 and WO/2021/063972.

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Glossary

Desmoplastic reaction

The growth of fibrous tissue around the tumour.

Dendritic cells

(DCs). Innate immune cells that respond to danger-associated molecular patterns and pathogen-associated molecular patterns, induce inflammation and can stimulate natural killer cells in the tumour microenvironment.

Thymocyte selection

Thymocytes (differentiating T cells in the thymus) are positively selected for weak binding to MHC molecules, and negatively selected (killed) if they bind MHC or self antigens too strongly. These processes are influenced by TGFβ.

Danger-associated molecular patterns or pathogen-associated molecular patterns

Molecules, molecular motifs or epitopes that are upregulated or exposed in the presence of pathogens or on damaged or dying cells. Specialized receptors on innate immune cells recognize these signals and trigger an inflammatory response.

Tumour-associated macrophages

A heterogeneous population in the tumour microenvironment originating from tissue-resident macrophages or monocytes.

Myeloid-derived suppressor cells

A heterogeneous group of myeloid immune cells that are characterized by their immunosuppressive functions. They can accumulate in cancer or infections, impinge on the function of other immune cells and are often poorly differentiated or immature.

Granulocytes

Also known as polymorphonuclear cells, a group of myeloid cells comprising neutrophils, basophils, eosinophils and mast cells.

Serrated CRC

A non-classical type of colorectal cancer (CRC) that derives from an alternative carcinogenesis pathway and has a sawtooth-like histological appearance.

Natural killer (NK) cells

Innate cytotoxic immune cells that can kill tumour cells (or pathogen-infected cells) without any priming or prior sensitization.

Antibody-dependent cellular cytotoxicity

Cell killing by virtue of target cell-specific antibodies and effector cells, such as natural killer cells, that express antibody receptors.

Innate lymphoid cells

(ILCs). Cells from the lymphoid lineage with innate immune functions, regulating other immune cells and producing signalling molecules. These lymphocytes without a T cell receptor are functionally analogous to T helper (TH) cells (TH1, TH2 and TH17 cells) and are classified accordingly (type 1, type 2 and type 3, respectively).

Plasmacytoid DCs

A subset of dendritic cells (DCs) that are found mostly in the circulation, lymph nodes and spleen. They have important roles in antiviral immunity and immune regulation, and are implicated in certain immune disorders.

MMTV-PyMT breast cancer mouse model

A mouse model of breast cancer generated by the mammary-specific expression of polyomavirus middle T antigen (PyMT), driven by a mouse mammary tumour virus (MMTV) element.

Chimeric switch receptor

Fusion proteins that link the binding of (immuno)inhibitory ligands to the activation of intracellular stimulatory signal elements, or vice versa.

In situ vaccination

The effect of therapeutically increasing the release of tumour-associated antigens, combined with innate immune cell activation, which results in (more) effective antigen presentation and T cell or B cell priming. Triggers include immunogenic cell death, radiotherapy and oncolytic viruses.

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Tauriello, D.V.F., Sancho, E. & Batlle, E. Overcoming TGFβ-mediated immune evasion in cancer. Nat Rev Cancer 22, 25–44 (2022). https://doi.org/10.1038/s41568-021-00413-6

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