Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1
Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1
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DOI：
10.1038/s41577-023-00867-9
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发表时间：
2023-04-25
影响因子：
100.3
通讯作者：
Honjo，Tasuku
中科院分区：
文献类型：
--
作者：
Chamoto，Kenji;Yaguchi，Tomonori;Honjo，Tasuku
PD1最初于1992年被发现，是一种与T细胞中活化诱导的细胞死亡相关的分子。在过去的30年里，人们发现PD1在避免过度激活诱导的细胞死亡和自身免疫中起着关键作用，而其抑制则释放抗癌免疫。在这里，我们概述了从发现PD1到其作为癌症免疫治疗突破性靶点的旅程。我们描述了它的调节和功能，并研究了PD1信号传导机制的理解如何表明在设置T细胞活化阈值中的中心功能，从而控制T细胞增殖，分化，耗竭和代谢状态。这种阈值理论，结合对T细胞代谢的新见解和对微生物群免疫细胞调节的更好理解，可以为开发有效的联合疗法提供指导。此外，我们还讨论了PD1靶向治疗后免疫相关不良事件的机制及其可能的治疗方法。
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.