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科学家发现抗GD2与抗CD47联合使用可介导肿瘤的根除
作者:小柯机器人 发布时间:2022/1/16 13:24:34

美国斯坦福大学医学院Robbie G. Majzner研究团队近期取得了新的研究进展,他们发现抗GD2与抗CD47联合使用可介导肿瘤的根除。相关论文发表在2022年1月13日出版的《自然—医学》杂志上。

在这里,研究人员在神经母细胞瘤的同基因和异种移植小鼠模型中建立了抗 GD2 和抗 CD47 组合的有效协同作用。在该模型中,抗GD2和抗CD47的联合应用可以根治骨肉瘤和小细胞肺癌,显著降低肿瘤负担并延长患者生存期。这种协同作用是由重新调整巨噬细胞活性平衡的两个 GD2 特异性因子驱动的。GD2在肿瘤细胞上的连接一方面导致表面钙网蛋白的上调(这是一种促吞噬细胞的“吃我”信号),促使细胞被清除,另一方面可以中断 GD2 与抑制性免疫受体 Siglec-7 的相互作用。这项工作证明了抗GD2和抗CD47的组合可用于临床转化,并表明CD47阻断与改变肿瘤微环境中额外的促吞噬和抗吞噬信号的单克隆抗体联合使用将是最有效的。

据介绍,双唾液酸神经节苷脂GD2在几种实体肿瘤中过表达,靶向GD2的单克隆抗体显著改善了高危神经母细胞瘤患儿的预后。然而,大约40%的神经母细胞瘤患者仍会复发,抗GD2在其他GD2+恶性肿瘤中并没有显著的临床活性。巨噬细胞是抗肿瘤免疫的重要媒介,但肿瘤通过表达检验点分子CD47(即所谓的“不要吃我”信号)来抵抗巨噬细胞的吞噬作用。

附:英文原文

Title: Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication

Author: Theruvath, Johanna, Menard, Marie, Smith, Benjamin A. H., Linde, Miles H., Coles, Garry L., Dalton, Guillermo Nicolas, Wu, Wei, Kiru, Louise, Delaidelli, Alberto, Sotillo, Elena, Silberstein, John L., Geraghty, Anna C., Banuelos, Allison, Radosevich, Molly Thomas, Dhingra, Shaurya, Heitzeneder, Sabine, Tousley, Aidan, Lattin, John, Xu, Peng, Huang, Jing, Nasholm, Nicole, He, Andy, Kuo, Tracy C., Sangalang, Emma R. B., Pons, Jaume, Barkal, Amira, Brewer, Rachel E., Marjon, Kristopher D., Vilches-Moure, Jose G., Marshall, Payton L., Fernandes, Ricardo, Monje, Michelle, Cochran, Jennifer R., Sorensen, Poul H., Daldrup-Link, Heike E., Weissman, Irving L., Sage, Julien, Majeti, Ravindra, Bertozzi, Carolyn R., Weiss, William A., Mackall, Crystal L., Majzner, Robbie G.

Issue&Volume: 2022-01-13

Abstract: The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2+ malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called ‘Don’t eat me’ signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic ‘Eat me’ signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.

DOI: 10.1038/s41591-021-01625-x

Source: https://www.nature.com/articles/s41591-021-01625-x

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex