Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1
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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Immune checkpoint inhibitors as monotherapy have limited efficacy in the treatment of relapsed/refractory multiple myeloma.
“However, the efficacy of these antibodies particularly as monotherapy was limited in the treatment of RRMM [173–176].”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [175]
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Multiple myeloma: signaling pathways and targeted therapy
Lu, Q., Yang, D., Li, H., Niu, T., & Tong, A. (2024) · Molecular biomedicine · doi:10.1186/s43556-024-00188-w · Cited by 90 · see citing works
- Authors
- Chamoto, K., Yaguchi, T., Tajima, M., & Honjo, T.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Honjo, Tasuku
- Venue
- Nature Reviews Immunology
- Published
- 2023-04-25
- Volume
- 23
- Issue
- 10
- Pages
- 682-695
- ISSN
- 1474-1733 (ISSN-L)
- 1474-1741
- OpenAlex
- W4366984847
- Cited by
- 185
- References
- 35
- Citations by year
- 2026: 50 · 2025: 59 · 2024: 62 · 2023: 14
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature reviews. Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (19K16881)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- PD-1, T cell activation threshold, T cell exhaustion, T cell metabolism, immune checkpoint blockade, cancer immunotherapy, autoimmunity, immune-related adverse events, microbiota, combination therapy
- MeSH terms
- Immune Checkpoint Inhibitors, Animals, Humans, Immunotherapy, Lymphocyte Activation, Neoplasms, T-Lymphocytes, Signal Transduction, Programmed Cell Death 1 Receptor
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