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Regulatory T cells in cancer immunosuppression — implications for anticancer therapy

Abstract

Regulatory T (Treg) cells, an immunosuppressive subset of CD4+ T cells characterized by the expression of the master transcription factor forkhead box protein P3 (FOXP3), are a component of the immune system with essential roles in maintaining self-tolerance. In addition, Treg cells can suppress anticancer immunity, thereby hindering protective immunosurveillance of neoplasia and hampering effective antitumour immune responses in tumour-bearing hosts, thus promoting tumour development and progression. Identification of the factors that are specifically expressed in Treg cells and/or that influence Treg cell homeostasis and function is important to understanding cancer pathogenesis and to identifying therapeutic targets. Immune-checkpoint inhibitors (ICIs) have provided a paradigm shift in the treatment of cancer. Most immune-checkpoint molecules are expressed in Treg cells, but the effects of ICIs on Treg cells, and thus the contributions of these cells to treatment responses, remain unclear. Notably, evidence indicates that ICIs targeting programmed cell death 1 (PD-1) might enhance the immunosuppressive function of Treg cells, whereas cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors might deplete these cells. Thus, although manipulation of Treg cells is a promising anticancer therapeutic strategy, approaches to controlling these cells require further research. Herein, we discuss novel insights into the roles of Treg cells in cancer, which can hopefully be used to develop Treg cell-targeted therapies and facilitate immune precision medicine.

Key points

  • Regulatory T (Treg) cells are a subset of CD4+ T cells with immunosuppressive effects through various cellular and humoral mechanisms: cytotoxic T lymphocyte antigen 4 (CTLA-4)-mediated suppression of antigen-presenting cells, consumption of IL-2 and production of immune inhibitory cytokines and molecules.

  • Treg cells can suppress antitumour immunity, thereby hindering immunosurveillance against cancer development in individuals without existing cancer and hampering effective antitumour immune responses in tumour-bearing hosts.

  • Treg cells with an activated phenotype can be enriched in tumours compared with peripheral blood, which is associated with a poor prognosis in patients with various types of cancer.

  • Programmed cell death 1 (PD-1) is a negative regulator of Treg cells as well as effector T cells, suggesting that PD-1 blockade enhances the suppressive function of Treg cells.

  • Treg cells more effectively suppress immune responses against self-antigens (shared antigens) than non-self-antigens (neoantigens).

  • Many Treg cell-targeted therapies are under investigation, although most of these treatments have limited efficacy in the clinic owing to the difficulty in selectively targeting Treg cells.

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Fig. 1: The development of Treg cells.
Fig. 2: Functional classification of human FOXP3+CD4+ T cells.
Fig. 3: Variable mechanisms of Treg cell-mediated immunosuppression.

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Acknowledgements

The work of the authors is supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Young Scientists grant 17J09900 and JSPS Research Fellow grant 17K18388 to Y.T. and S grant 17H06162 and Challenging Exploratory Research grant 16K15551 to H.N.); the Naito Foundation (to Y.T. and H.N.); the SGH Foundation (to Y.T.); the Japan Agency for Medical Research and Development (AMED; Therapeutic Evolution (P-CREATE) grant 16cm0106301h0002 to H.N.); and the National Cancer Centre Research and Development Fund (grant 28-A-7 to H.N.).

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Nature Reviews Clinical Oncology thanks T. Whiteside and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Correspondence to Hiroyoshi Nishikawa.

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Y.T. has received honoraria and grants from Bristol-Myers Squibb, Novartis, Ono, Taiho and Takeda, a grant from AstraZeneca and honoraria from Boehringer Ingelheim. K.S. has received advisory fees and grants from Astellas, Lilly and Ono, grants from Chugai, Daiichi Sankyo, Dainippon Sumitomo, Merck Sharp & Dohme and Taiho and advisory fees from Bristol-Myers Squibb, Pfizer and Takeda. H.N. has received honoraria and grants from Bristol-Myers Squibb, Chugai and Ono and grants from Astellas, BD Japan, Daiichi Sankyo, Kyowa Hakko Kirin, Sysmex, Taiho and Zenyaku Kogyo.

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Togashi, Y., Shitara, K. & Nishikawa, H. Regulatory T cells in cancer immunosuppression — implications for anticancer therapy. Nat Rev Clin Oncol 16, 356–371 (2019). https://doi.org/10.1038/s41571-019-0175-7

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