Abstract:
Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of NF1 and dysregulation of RAS-MAPK signaling in Schwann cells. Most PNFs shrink in response to MEK inhibition, but targets with increased and durable effects are needed. We identified the anaphylatoxin C5a as increased in PNFs and expressed largely by PNF m acrophages. We defined pharmacokinetic and immunomodulatory properties of a C5aR1/2 antagonist and tested if peptide antagonists augment the effects of MEK inhibition. MEK inhibition recruited C5AR1 to the macrophage surface; short-term inhibition of C5aR elevated macrophage apoptosis and Schwann cell death, without affecting MEK-induced tumor shrinkage. PNF macrophages lacking C5aR1 increased the engulfment of dying Schwann cells, allowing their visualization. Halting combination therapy resulted in altered T-cell distribution, elevated Iba1+ and CD169+ immunoreactivity, and profoundly altered cytokine expression, but not sustained trumor shrinkage. Thus, C5aRA inhibition independently induces macrophage cell death and causes sustained and durable effects on the PNF microenvironment.
摘要:
丛状神经纤维瘤(PNFs)是由Schwann细胞中NF1的丧失和RAS-MAPK信号传导失调引起的神经肿瘤。大多数PNFs响应于MEK抑制而收缩,但是需要具有增加和持久效果的目标。我们确定了过敏毒素C5a在PNFs中增加,并且主要由PNFm巨噬细胞表达。我们定义了C5aR1/2拮抗剂的药代动力学和免疫调节特性,并测试了肽拮抗剂是否增强了MEK抑制作用。MEK抑制将C5AR1募集到巨噬细胞表面;C5aR的短期抑制提高了巨噬细胞凋亡和雪旺细胞死亡,不影响MEK诱导的肿瘤收缩。缺乏C5aR1的PNF巨噬细胞增加了垂死的雪旺细胞的吞噬,允许他们的可视化。停止联合治疗导致T细胞分布改变,Iba1+和CD169+免疫反应性升高,并深刻改变了细胞因子的表达,但不是持续的喇叭收缩。因此,C5aRA抑制独立地诱导巨噬细胞死亡并对PNF微环境造成持续和持久的影响。