Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, 94305, USA.
Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA.
Cell Death Dis. 2019 Jan 15;10(2):36. doi: 10.1038/s41419-018-1285-3.
CD47 monoclonal antibodies (mAbs) activate tumor-associated macrophages (TAMs) in sarcomas to phagocytose and eliminate cancer cells. Though CD47 mAbs have entered clinical trials, diagnostic tests for monitoring therapy response in vivo are currently lacking. Ferumoxytol is an FDA-approved iron supplement which can be used "off label" as a contrast agent: the nanoparticle-based drug is phagocytosed by TAM and can be detected with magnetic resonance imaging (MRI). We evaluated if ferumoxytol-enhanced MRI can monitor TAM response to CD47 mAb therapy in osteosarcomas. Forty-eight osteosarcoma-bearing mice were treated with CD47 mAb or control IgG and underwent pre- and post-treatment ferumoxytol-MRI scans. Tumor enhancement, quantified as T2 relaxation times, was compared with the quantity of TAMs as determined by immunofluorescence microscopy and flow cytometry. Quantitative data were compared between experimental groups using exact two-sided Wilcoxon rank-sum tests. Compared to IgG-treated controls, CD47 mAb-treated tumors demonstrated significantly shortened T2 relaxation times on ferumoxytol-MRI scans (p < 0.01) and significantly increased F4/80+CD80+ M1 macrophages on histopathology (p < 0.01). CD47 mAb-treated F4/80+ macrophages demonstrated significantly augmented phagocytosis of ferumoxytol nanoparticles (p < 0.01). Thus, we conclude that ferumoxytol-MRI can detect TAM response to CD47 mAb in mouse models of osteosarcoma. The ferumoxytol-MRI imaging test could be immediately applied to monitor CD47 mAb therapies in clinical trials.
CD47 单克隆抗体 (mAb) 可激活肉瘤中的肿瘤相关巨噬细胞 (TAM) 吞噬并消除癌细胞。尽管 CD47 mAb 已进入临床试验，但目前缺乏用于体内监测治疗反应的诊断测试。Ferumoxytol 是一种获得 FDA 批准的铁补充剂，可“超适应证”用作造影剂：基于纳米颗粒的药物被 TAM 吞噬，并可通过磁共振成像 (MRI) 检测到。我们评估了 Ferumoxytol 增强 MRI 是否可监测 CD47 mAb 治疗骨肉瘤中 TAM 的反应。48 只骨肉瘤荷瘤小鼠接受 CD47 mAb 或对照 IgG 治疗，并进行治疗前后 Ferumoxytol-MRI 扫描。通过免疫荧光显微镜和流式细胞术确定 TAM 的数量，并将肿瘤增强（以 T2 弛豫时间量化）与 TAM 的数量进行比较。使用精确双边 Wilcoxon 秩和检验比较实验组之间的定量数据。与 IgG 治疗的对照组相比，CD47 mAb 治疗的肿瘤在 Ferumoxytol-MRI 扫描上显示出明显缩短的 T2 弛豫时间（p<0.01），组织病理学上的 F4/80+CD80+M1 巨噬细胞明显增加（p<0.01）。CD47 mAb 治疗的 F4/80+巨噬细胞显示出 Ferumoxytol 纳米颗粒吞噬作用的明显增强（p<0.01）。因此，我们得出结论，Ferumoxytol-MRI 可检测骨肉瘤小鼠模型中 TAM 对 CD47 mAb 的反应。Ferumoxytol-MRI 成像测试可立即应用于监测临床试验中的 CD47 mAb 治疗。
