针对 CSF1/CSF1R 轴是治疗恶性脑膜瘤的一种潜在治疗策略。
Targeting the CSF1/CSF1R axis is a potential treatment strategy for malignant meningiomas.
机构信息
Department of Neurological Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
出版信息
Neuro Oncol. 2021 Nov 2;23(11):1922-1935. doi: 10.1093/neuonc/noab075.
BACKGROUND
Malignant meningiomas are fatal and lack effective therapy. As M2 macrophages are the most prevalent immune cell type in human meningiomas, we hypothesized that normalizing this immunosuppressive population would be an effective treatment strategy.
METHODS
We used CIBERSORTx to examine the proportions of 22 immune subsets in human meningiomas. We targeted the colony-stimulating factor 1 (CSF1) or CSF1 receptor (CSF1R) axis, an important regulator of macrophage phenotype, using monoclonal antibodies (mAbs) in a novel immunocompetent murine model (MGS1) for malignant meningioma. RNA sequencing (RNA-seq) was performed to identify changes in gene expression in the tumor microenvironment (TME). Mass cytometry was used to delineate changes in immune subsets after treatment. We measured patients' plasma CSF1 levels using ELISA and CSF1R expression using multiplex quantitative immunofluorescence in a human meningioma tissue microarray.
RESULTS
Human meningiomas are heavily enriched for immunosuppressive myeloid cells. MGS1 recapitulates the TME of human meningiomas, including an abundance of myeloid cells, a paucity of infiltrating T cells, and low programmed death ligand 1 (PD-L1) expression. Treatment of murine meningiomas with anti-CSF1/CSF1R, but not programmed cell death receptor 1 (PD-1), mAbs abrogate tumor growth. RNA-seq and mass cytometry analyses reveal a myeloid cell reprogramming with limited effect on T cells in the TME. CSF1 plasma levels are significantly elevated in human patients, and CSF1R is highly expressed on CD163+ macrophages within the human TME.
CONCLUSION
Our findings suggest that anti-CSF1/CSF1R antibody treatment may be an effective normalization cancer immunotherapy for malignant meningiomas.
背景
恶性脑膜瘤是致命的，缺乏有效的治疗方法。由于 M2 巨噬细胞是人类脑膜瘤中最常见的免疫细胞类型，我们假设使这种免疫抑制性群体正常化将是一种有效的治疗策略。
方法
我们使用 CIBERSORTx 检查了人类脑膜瘤中 22 种免疫亚群的比例。我们使用针对集落刺激因子 1（CSF1）或 CSF1 受体（CSF1R）轴的单克隆抗体（mAb），在一种新的免疫活性小鼠模型（MGS1）中靶向恶性脑膜瘤。进行 RNA 测序（RNA-seq）以鉴定肿瘤微环境（TME）中基因表达的变化。使用质谱流式细胞术在治疗后描绘免疫亚群的变化。我们使用 ELISA 测量患者的血浆 CSF1 水平，并使用人类脑膜瘤组织微阵列中的多重定量免疫荧光测量 CSF1R 表达。
结果
人类脑膜瘤富含免疫抑制性髓样细胞。MGS1 重现了人类脑膜瘤的 TME，包括丰富的髓样细胞，浸润性 T 细胞稀少和程序性死亡配体 1（PD-L1）表达低。用抗 CSF1/CSF1R，而不是程序性死亡受体 1（PD-1）mAb 治疗鼠脑膜瘤可阻止肿瘤生长。RNA-seq 和质谱流式细胞术分析揭示了 TME 中髓样细胞的重编程，对 T 细胞的影响有限。人类患者的 CSF1 血浆水平显着升高，CSF1R 在人类 TME 中的 CD163+巨噬细胞上高度表达。
结论
我们的发现表明，抗 CSF1/CSF1R 抗体治疗可能是恶性脑膜瘤的有效正常化癌症免疫疗法。
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