Abstract：
Cancer treatment with anti-PD-1 immunotherapy can cause central nervous system immune-related adverse events (CNS-irAEs). The role of microglia in anti-PD-1 immunotherapy-induced CNS-irAEs is unclear. We found that anti-PD-1 treatment of mice caused morphological signs of activation and major histocompatibility complex (MHC) class II up-regulation on microglia. Functionally, anti-PD-1 treatment induced neurocognitive deficits in mice, independent of T cells, B cells, and natural killer cells. Instead, we found that microglia mediated these CNS-irAEs. Single-cell RNA sequencing revealed major transcriptional changes in microglia upon anti-PD-1 treatment. The anti-PD-1 effects were mediated by anti-PD-1 antibodies interacting directly with microglia and were not secondary to peripheral T cell activation. Using a proteomics approach, we identified spleen tyrosine kinase (Syk) as a potential target in activated microglia upon anti-PD-1 treatment. Syk inhibition reduced microglia activation and improved neurocognitive function without impairing anti-melanoma effects. Moreover, we analyzed CNS tissue from a patient cohort that had received anti-PD-1 treatment. Imaging mass cytometry revealed that anti-PD-1 treatment of patients was associated with increased surface marker expression indicative of microglia activation. In summary, we identified a disease-promoting role for microglia in CNS-irAEs driven by Syk and provide an inhibitor-based approach to interfere with this complication after anti-PD-1 immunotherapy.
摘要：
使用抗PD-1免疫疗法的癌症治疗可导致中枢神经系统免疫相关不良事件(CNS-irAEs)。小胶质细胞在抗PD-1免疫疗法诱导的CNS-irAE中的作用尚不清楚。我们发现小鼠的抗PD-1治疗引起小胶质细胞活化和主要组织相容性复合物(MHC)II类上调的形态学征象。功能上,抗PD-1治疗诱导小鼠神经认知缺陷，独立于T细胞，B细胞,和自然杀伤细胞。相反，我们发现小胶质细胞介导这些CNS-irAE。单细胞RNA测序揭示了抗PD-1治疗后小胶质细胞的主要转录变化。抗PD-1效应是由与小胶质细胞直接相互作用的抗PD-1抗体介导的,并且不是继发于外周T细胞活化。使用蛋白质组学方法，我们确定脾酪氨酸激酶(Syk)是抗PD-1治疗后活化小胶质细胞的潜在靶点.Syk抑制减少小胶质细胞激活并改善神经认知功能而不损害抗黑色素瘤作用。此外，我们分析了接受抗PD-1治疗的患者队列的CNS组织.成像质量细胞计数显示，患者的抗PD-1治疗与指示小胶质细胞活化的表面标志物表达增加有关。总之,我们确定了小胶质细胞在Syk驱动的CNS-irAE中的疾病促进作用,并提供了一种基于抑制剂的方法来干扰抗PD-1免疫治疗后的这种并发症.
