Anti-PD-1 therapy can induce eradication of tumors and immune-related adverse events (irAEs) in humans and model animals. However, how anti-PD-1 therapy modifies cellular phenotypes of CD8+ T cells to destroy tumors and damage self-tissues remains to be clarified. Here we performed single cell mRNA expression profiling of autoreactive CD8+ T cells under or beyond PD-1 suppression in target tissues and reconstructed their activation trajectory. Autoreactive CD8+ T cells went through four activation phases and PD-1 strongly attenuated the transition from the second- to the third-phase, where effector functions were acquired. Shifts in cluster composition of autoreactive CD8+ T cells markedly reflected the severity of autoimmunity. In addition, genes up-regulated along the activation-trajectory in autoimmunity were highly expressed in responders of melanoma patients in anti-PD-1 therapy, suggesting that tumor-specific T cells need to be activated in a similar trajectory to destroy tumors in human patients upon PD-1 blockade. These findings reveal that PD-1 blockade facilitates the activation trajectory of CD8+ T cells to boost their effector functions. Targeted manipulation of the trajectory could lead to new therapeutic opportunities.

中文翻译：

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PD-1中止了自身反应性CD8 + T细胞的激活轨迹，以阻止其获得效应子功能。

抗PD-1治疗可以在人类和模型动物中消除肿瘤和免疫相关的不良事件（irAEs）。然而，抗PD-1疗法如何修饰CD8 + T细胞的细胞表型以破坏肿瘤和破坏自身组织尚待阐明。在这里，我们对目标组织中PD-1抑制作用下或以上的自身反应性CD8 + T细胞进行了单细胞mRNA表达谱分析，并重建了它们的激活轨迹。自身反应性CD8 + T细胞经历了四个激活阶段，PD-1大大减弱了从第二阶段到第三阶段的转变，在此阶段获得了效应子功能。自身反应性CD8 + T细胞簇组成的变化明显反映了自身免疫的严重程度。此外，在抗PD-1治疗的黑色素瘤患者的应答者中，沿自身免疫激活途径上调的基因高度表达，这表明肿瘤特异性T细胞需要在相似的途径中被激活，才能在PD时破坏人类患者的肿瘤-1封锁。这些发现表明，PD-1阻断促进了CD8 + T细胞的激活轨迹，从而增强了其效应功能。轨迹的目标操纵可能会带来新的治疗机会。