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.

中文翻译：

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C5aR 加上 MEK 抑制可持久靶向肿瘤环境并揭示肿瘤细胞的吞噬作用。

丛状神经纤维瘤 (PNF) 是由雪旺细胞中NF1缺失和 RAS-MAPK 信号传导失调引起的神经肿瘤。大多数 PNF 会因 MEK 抑制而收缩，但需要具有增强且持久效果的靶标。我们发现过敏毒素 C5a 在 PNF 中增加，并且主要由 PNF m 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 MEK 抑制的效果。MEK 抑制将 C5AR1 招募到巨噬细胞表面；短期抑制 C5aR 会增加巨噬细胞凋亡和雪旺细胞死亡，而不影响 MEK 诱导的肿瘤缩小。缺乏 C5aR1 的 PNF 巨噬细胞增加了对垂死雪旺细胞的吞噬，从而使它们可视化。停止联合治疗会导致 T 细胞分布改变、Iba1+ 和 CD169+ 免疫反应性升高，并显着改变细胞因子表达，但肿瘤不会持续缩小。因此，C5aRA 抑制独立诱导巨噬细胞死亡并对 PNF 微环境产生持续和持久的影响。