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TGFβ biology in cancer progression and immunotherapy

Nature Reviews Clinical Oncology volume 18, pages 9–34 (2021)Cite this article

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Abstract

TGFβ signalling has key roles in cancer progression: most carcinoma cells have inactivated their epithelial antiproliferative response and benefit from increased TGFβ expression and autocrine TGFβ signalling through effects on gene expression, release of immunosuppressive cytokines and epithelial plasticity. As a result, TGFβ enables cancer cell invasion and dissemination, stem cell properties and therapeutic resistance. TGFβ released by cancer cells, stromal fibroblasts and other cells in the tumour microenvironment further promotes cancer progression by shaping the architecture of the tumour and by suppressing the antitumour activities of immune cells, thus generating an immunosuppressive environment that prevents or attenuates the efficacy of anticancer immunotherapies. The repression of TGFβ signalling is therefore considered a prerequisite and major avenue to enhance the efficacy of current and forthcoming immunotherapies, including in tumours comprising cancer cells that are not TGFβ responsive. Herein, we introduce the mechanisms underlying TGFβ signalling in tumours and their microenvironment and discuss approaches to inhibit these signalling mechanisms as well as the use of these approaches in cancer immunotherapies and their potential adverse effects.

Key points

  • TGFβ released and activated by malignant and non-cancer cells within the tumour microenvironment (TME) promotes cancer progression through highly regulated and differential effects on multiple cell types.

  • Enhanced TGFβ signalling promotes cancer cell invasion, dissemination and stem cell properties, and suppresses the sensitivity to anticancer drugs.

  • TGFβ shapes the TME through effects on cancer-associated fibroblasts, endothelial cells and pericytes, tumour architecture and suppression of protective immune cell functions.

  • TGFβ signalling in the TME represses the antitumour functions of various immune cell populations, including T cells and natural killer cells; the resulting immune suppression severely limits the efficacy of immune-checkpoint inhibitors and other immunotherapeutic approaches.

  • Inhibition of TGFβ signalling is currently being evaluated in multiple clinical trials as a major avenue to enhance the efficacy of cancer immunotherapies but systemic adverse effects and the therapeutic index need careful consideration.

  • Diverse approaches towards more selective inhibition of TGFβ activation or signalling are being actively pursued in order to enhance effectiveness and reduce the toxicity of a diverse array of cancer immunotherapies.

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Fig. 1: Cell type heterogeneity within the tumour microenvironment.
Fig. 2: Latent TGFβ activation and initiation of TGFβ signalling through its receptors and Smad proteins.
Fig. 3: Epithelial plasticity of carcinoma cells in response to TGFβ.
Fig. 4: Effects of TGFβ on immune cell populations.
Fig. 5: Response of cancer-associated fibroblasts and endothelial cells to TGFβ.
Fig. 6: Anti-TGFβ therapy potentiates infiltration of T cells into the tumour core.

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Authors and Affiliations

  1. Department of Cell and Tissue Biology, University of California at San Francisco (UCSF), San Francisco, CA, USA

    Rik Derynck

  2. Department of Anatomy, UCSF, San Francisco, CA, USA

    Rik Derynck & Rosemary J. Akhurst

  3. Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA, USA

    Rik Derynck & Rosemary J. Akhurst

  4. Department of Cancer Immunology, Genentech, South San Francisco, CA, USA

    Shannon J. Turley

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The authors contributed equally to all aspects of the article.

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Correspondence to Rik Derynck, Shannon J. Turley or Rosemary J. Akhurst.

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Competing interests

R.D. is a co-founder of Pliant Therapeutics. S.J.T. is an employee of Genentech. R.J.A. has sponsored research agreements with Pfizer and Bristol–Myers Squibb and is a co-inventor of a patent on the use of anti-TGFβ antibodies that is co-owned by the University of California at San Francisco and XOMA.

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Nature Reviews Clinical Oncology thanks S. Mani, J. Seoane, H. Ungefroren and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Derynck, R., Turley, S.J. & Akhurst, R.J. TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol 18, 9–34 (2021). https://doi.org/10.1038/s41571-020-0403-1

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