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  • Review Article
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Regulatory T cell-mediated immunosuppression orchestrated by cancer: towards an immuno-genomic paradigm for precision medicine

Nature Reviews Clinical Oncology volume 21, pages 337–353 (2024)Cite this article

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Abstract

Accumulating evidence indicates that aberrant signalling stemming from genetic abnormalities in cancer cells has a fundamental role in their evasion of antitumour immunity. Immune escape mechanisms include enhanced expression of immunosuppressive molecules, such as immune-checkpoint proteins, and the accumulation of immunosuppressive cells, including regulatory T (Treg) cells, in the tumour microenvironment. Therefore, Treg cells are key targets for cancer immunotherapy. Given that therapies targeting molecules predominantly expressed by Treg cells, such as CD25 or GITR, have thus far had limited antitumour efficacy, elucidating how certain characteristics of cancer, particularly genetic abnormalities, influence Treg cells is necessary to develop novel immunotherapeutic strategies. Hence, Treg cell-targeted strategies based on the particular characteristics of cancer in each patient, such as the combination of immune-checkpoint inhibitors with molecularly targeted agents that disrupt the immunosuppressive networks mediating Treg cell recruitment and/or activation, could become a new paradigm of cancer therapy. In this Review, we discuss new insights on the mechanisms by which cancers generate immunosuppressive networks that attenuate antitumour immunity and how these networks confer resistance to cancer immunotherapy, with a focus on Treg cells. These insights lead us to propose the concept of ‘immuno-genomic precision medicine’ based on specific characteristics of cancer, especially genetic profiles, that correlate with particular mechanisms of tumour immune escape and might, therefore, inform the optimal choice of immunotherapy for individual patients.

Key points

  • Regulatory T (Treg) cells are an immunosuppressive subset of CD4+ T cells and have important activities that restrain antitumour immune responses, making them a potential therapeutic target for cancer immunotherapy.

  • An abundance of Treg cells in the tumour microenvironment (TME) correlates with unfavourable patient survival across various cancer types, and PD-1 expression on intratumoural Treg cells is associated with resistance to treatment with anti-PD-(L)1 antibodies.

  • Treg cells accumulate in the TME via multiple mechanisms orchestrated by cancer cells, including chemokine production, generation of a favourable metabolic milieu and antigenic stimulation.

  • The immunosuppressive TME with abundant Treg cells generated by signalling downstream of driver oncogenes in cancer cells as a consequence of ‘immuno-genomic cancer evolution’ could be manipulated using certain molecularly targeted agents.

  • Immuno-genome precision medicine in which cancer immunotherapy is combined in an individualized manner with molecularly targeted agents that disrupt immunosuppressive cancer networks might improve patient outcomes across multiple cancer types.

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Fig. 1: Key characteristics of regulatory T cells in the tumour microenvironment.
Fig. 2: Mechanisms of PD-1 expression in intratumoural regulatory T cells.
Fig. 3: Multiple mechanisms of regulatory T cell accumulation and activation in tumours.

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Acknowledgements

The authors express special thanks to all patients, their families and all investigators who participated in their translational studies.

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  1. These authors contributed equally: Shogo Kumagai, Kota Itahashi.

Authors and Affiliations

  1. Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo, Japan

    Shogo Kumagai, Kota Itahashi & Hiroyoshi Nishikawa

  2. Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan

    Shogo Kumagai, Kota Itahashi & Hiroyoshi Nishikawa

  3. Division of Cellular Signalling, Research Institute, National Cancer Center, Tokyo, Japan

    Shogo Kumagai

  4. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Hiroyoshi Nishikawa

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S.K. has received honoraria for lectures from Chugai Pharmaceutical and Merck Sharp & Dohme (MSD) outside the submitted work. H.N. has received research funding and honoraria for lectures from Bristol Myers Squibb, Chugai Pharmaceutical, MSD and Ono Pharmaceuticals; honoraria for lectures from Amgen; and research funding from Asahi-Kasei, Astellas Pharma, BD Japan, Daiichi Sankyo, Debiopharma, Fujifilm, Kyowa Kirin, Oncolys BioPharma, Sisco Research Laboratories (SRL), Sumitomo Dainippon Pharma, Sysmex, Taiho Pharmaceutical and Zenyaku Kogyo outside this work. H.N. is also a board member and a founder of ARC Therapies and a scientific adviser of LTZ Therapeutics. K.I. declares no competing interests.

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Kumagai, S., Itahashi, K. & Nishikawa, H. Regulatory T cell-mediated immunosuppression orchestrated by cancer: towards an immuno-genomic paradigm for precision medicine. Nat Rev Clin Oncol 21, 337–353 (2024). https://doi.org/10.1038/s41571-024-00870-6

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