阻断 CD47 可有效增强抗血管生成治疗在非小细胞肺癌中的疗效。
Blocking CD47 efficiently potentiated therapeutic effects of anti-angiogenic therapy in non-small cell lung cancer.
机构信息
Minhang Hospital, Fudan University, 170 Xinsong Road, Shanghai, 201199, China.
Department of Microbiological and Biochemical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China.
出版信息
J Immunother Cancer. 2019 Dec 11;7(1):346. doi: 10.1186/s40425-019-0812-9.
BACKGROUND
Inhibitors targeting VEGF and VEGFR are commonly used in the clinic, but only a subset of patients could benefit from these inhibitors and the efficacy was limited by multiple relapse mechanisms. In this work, we aimed to investigate the role of innate immune response in anti-angiogenic therapy and explore efficient therapeutic strategies to enhance efficacy of anti-angiogenic therapy against non-small cell lung cancer (NSCLC).
METHODS
Three NSCLC tumor models with responses to VEGF inhibitors were designed to determine innate immune-related underpinnings of resistance to anti-angiogenic therapy. Immunofluorescence staining, fluorescence-activated cell sorting and immunoblot analysis were employed to reveal the expression of immune checkpoint regulator CD47 in refractory NSCLC. Metastatic xenograft models and VEGFR1-SIRPα fusion protein were applied to evaluate the therapeutic effect of simultaneous disruption of angiogenetic axis and CD47-SIRPα axis.
RESULTS
Up-regulation of an innate immunosuppressive pathway, CD47, the ligand of the negative immune checkpoint regulator SIRPα (signal regulatory protein alpha), was observed in NSCLC tumors during anti-angiogenic therapy. Further studies revealed that CD47 upregulation in refractory lung tumor models was mediated by TNF-α/NF-κB1 signal pathway. Targeting CD47 could trigger macrophage-mediated elimination of the relapsed NSCLC cells, eliciting synergistic anti-tumor effect. Moreover, simultaneously targeting VEGF and CD47 by VEGFR1-SIRPα fusion protein induced macrophages infiltration and sensitized NSCLC to angiogenesis inhibitors and CD47 blockade.
CONCLUSIONS
Our research provided evidence that CD47 blockade could sensitize NSCLC to anti-angiogenic therapy and potentiate its anti-tumor effects by enhancing macrophage infiltration and tumor cell destruction, providing novel therapeutics for NSCLC by disrupting CD47/SIRPα interaction and angiogenetic axis.
背景
针对 VEGF 和 VEGFR 的抑制剂在临床上被广泛应用，但只有一部分患者能够从这些抑制剂中受益，而且疗效受到多种复发机制的限制。在这项工作中，我们旨在研究先天免疫反应在抗血管生成治疗中的作用，并探索有效的治疗策略，以增强抗血管生成治疗对非小细胞肺癌（NSCLC）的疗效。
方法
设计了三个对 VEGF 抑制剂有反应的 NSCLC 肿瘤模型，以确定对抗血管生成治疗产生耐药性的先天免疫相关基础。采用免疫荧光染色、荧光激活细胞分选和免疫印迹分析来揭示免疫检查点调节剂 CD47 在难治性 NSCLC 中的表达。转移异种移植模型和 VEGFR1-SIRPα 融合蛋白被用于评估同时破坏血管生成轴和 CD47-SIRPα 轴的治疗效果。
结果
在抗血管生成治疗过程中，我们观察到 NSCLC 肿瘤中存在一种先天免疫抑制途径的上调，即 CD47，它是负免疫检查点调节剂 SIRPα（信号调节蛋白α）的配体。进一步的研究表明，在难治性肺肿瘤模型中，CD47 的上调是由 TNF-α/NF-κB1 信号通路介导的。靶向 CD47 可以触发巨噬细胞介导的复发 NSCLC 细胞的消除，从而产生协同的抗肿瘤效应。此外，通过 VEGFR1-SIRPα 融合蛋白同时靶向 VEGF 和 CD47，可诱导巨噬细胞浸润，并使 NSCLC 对血管生成抑制剂和 CD47 阻断敏感。
结论
我们的研究提供了证据表明，CD47 阻断可以通过增强巨噬细胞浸润和肿瘤细胞破坏，使 NSCLC 对抗血管生成治疗敏感，并增强其抗肿瘤效果，通过破坏 CD47/SIRPα 相互作用和血管生成轴，为 NSCLC 提供了新的治疗策略。
Zotero 插件