TCR ligand potency differentially impacts PD-1 inhibitory effects on diverse signaling pathways.
TCR ligand potency differentially impacts PD-1 inhibitory effects on diverse signaling pathways.
复制标题
TCR 配体效力对不同信号通路的 PD-1 抑制作用有不同的影响。
DOI：
10.1084/jem.20231242
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
G
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文献类型：
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作者：
Chan,Waipan;Cao,YuqiM;Zhao,Xiang;Schrom,EdwardC;Jia,Dongya;Song,Jian;Sibener,LeahV;Dong,Shen;Fernandes,RicardoA;Bradfield,ClintonJ;Smelkinson,Margery;Kabat,Juraj;Hor,JyhLiang;Altan-Bonnet,Grégoire;Garcia,KChristopher;G
检查点阻断彻底改变了癌症治疗，但我们仍然缺乏对抑制性受体如何影响不同信号通路的定量、机制性理解。为了解决这个问题，我们开发并应用了荧光细胞内活多重信号转导活性报告（FILMSTAR）系统来分析PD-1诱导的抑制作用。这些研究确定了仅由TCR触发或需要TCR和CD 28输入的途径。使用PD-L1和CD 80表达不同的呈递细胞，同时显示不同效力的TCR配体，我们发现PD-1介导的抑制主要以对肽配体质量高度敏感的方式靶向TCR相关信号。这些发现有助于解决现有数据中关于T细胞中PD-1抑制位点的差异，同时强调新抗原效力在控制检查点治疗效果方面的重要性。
Checkpoint blockade revolutionized cancer therapy, but we still lack a quantitative, mechanistic understanding of how inhibitory receptors affect diverse signaling pathways. To address this issue, we developed and applied a fluorescent intracellular live multiplex signal transduction activity reporter (FILMSTAR) system to analyze PD-1-induced suppressive effects. These studies identified pathways triggered solely by TCR or requiring both TCR and CD28 inputs. Using presenting cells differing in PD-L1 and CD80 expression while displaying TCR ligands of distinct potency, we found that PD-1-mediated inhibition primarily targets TCR-linked signals in a manner highly sensitive to peptide ligand quality. These findings help resolve discrepancies in existing data about the site(s) of PD-1 inhibition in T cells while emphasizing the importance of neoantigen potency in controlling the effects of checkpoint therapy.