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Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1

Nature Reviews Immunology volume 23, pages 682–695 (2023)Cite this article

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Abstract

PD1 was originally discovered in 1992 as a molecule associated with activation-induced cell death in T cells. Over the past 30 years, it was found that PD1 has a critical role in avoiding overactivation-induced cell death and autoimmunity, whereas its inhibition unleashes anticancer immunity. Here, we outline the journey from the discovery of PD1 to its role as a breakthrough target in cancer immunotherapy. We describe its regulation and function and examine how a mechanistic understanding of PD1 signalling suggests a central function in setting the T cell activation threshold, thereby controlling T cell proliferation, differentiation, exhaustion and metabolic status. This threshold theory, in combination with new insights into T cell metabolism and a better understanding of immune cell modulation by the microbiota, can provide guidance for the development of efficient combination therapies. Moreover, we discuss the mechanisms underlying immune-related adverse events after PD1-targeted therapy and their possible treatment.

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Fig. 1: Mechanisms of PD1 regulation.
Fig. 2: Regulation of the T cell activation threshold through PD1 or CTLA4 blockade.
Fig. 3: Mitochondrial metabolism controls fate in T cell differentiation.

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Acknowledgements

We thank S. Fagarasan, F. Matsuda and N. Minato for their long support and collaboration. This work was supported by the Japan Agency for Medical Research and Development under Grant Number 20cm0106302 (T.H.), 22zf0127004s0202 and 22ama221305 (K.C.); JSPS KAKENHI grant under Grant Number JP21H03087 (K.C.), JP21H02785 (T.Y.) and JP19K16881 (M.T.); Tang Prize Foundation (T.H.); Yanai Fund (T.H.); Meiji Holdings Co., Ltd (T.H.); Meiji Seika Pharma Co., Ltd (T.H.); and Bristol-Myers Squibb Company (T.H.).

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  1. These authors contributed equally: Kenji Chamoto, Tomonori Yaguchi, Masaki Tajima.

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  1. Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kenji Chamoto, Tomonori Yaguchi & Tasuku Honjo

  2. Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Masaki Tajima

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Chamoto, K., Yaguchi, T., Tajima, M. et al. Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1. Nat Rev Immunol 23, 682–695 (2023). https://doi.org/10.1038/s41577-023-00867-9

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  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-023-00867-9

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