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

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,...

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Published inNature reviews. Immunology Vol. 23; no. 10; pp. 682 - 695
Main Authors Chamoto, Kenji, Yaguchi, Tomonori, Tajima, Masaki, Honjo, Tasuku
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.10.2023
Nature Publishing Group
Subjects
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Apoptosis
Autoimmunity
Biomedical and Life Sciences
Biomedicine
Cancer immunotherapy
Cell activation
Cell death
Cell differentiation
Cell proliferation
Immunology
Immunotherapy
Lymphocytes
Lymphocytes T
PD-1 protein
Perspective
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Summary: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. In this Perspective, Honjo and co-workers describe the discovery of PD1 and its journey to become a major target for cancer immunotherapy. It discusses the complex regulatory systems that govern PD1 expression as well as recent insights into PD1 function and the mechanisms of PD1-blocking therapies.
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ISSN:1474-1733
1474-1741
DOI:10.1038/s41577-023-00867-9