https://ror.org/01hcyya48 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
Life Sci Alliance. 2024 Mar 8;7(5). doi: 10.26508/lsa.202302229. Print 2024 May.
Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of 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.
丛状神经纤维瘤（PNFs）是由施旺细胞中 RAS-MAPK 信号通路的缺失和失调引起的神经肿瘤。大多数 PNFs 在 MEK 抑制后会缩小，但需要具有增加和持久效果的靶点。我们发现过敏毒素 C5a 在 PNFs 中增加，并主要由 PNF 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 募集到巨噬细胞表面；C5aR 的短期抑制会增加巨噬细胞凋亡和施旺细胞死亡，而不影响 MEK 诱导的肿瘤缩小。缺乏 C5aR1 的 PNF 巨噬细胞增加了对死亡施旺细胞的吞噬作用，使其能够被可视化。停止联合治疗会导致 T 细胞分布改变、Iba1+和 CD169+免疫反应性升高以及细胞因子表达发生深刻改变，但不能持续缩小肿瘤。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。
