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.

双唾液酸神经节苷脂 GD2 在多种实体瘤中过度表达，针对 GD2 的单克隆抗体显着改善了高危神经母细胞瘤儿童的预后。然而，大约 40% 的神经母细胞瘤患者仍然会复发，并且抗 GD2 药物在任何其他 GD2 ⁺恶性肿瘤中并未介导显着的临床活性。巨噬细胞是抗肿瘤免疫的重要介质，但肿瘤通过表达检查点分子 CD47（所谓的“别吃我”信号）来抵抗巨噬细胞的吞噬作用。在这项研究中，我们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，其中该组合可以根除肿瘤，以及骨肉瘤和小细胞肺癌，其中该组合显着减少肿瘤负担并延长生存期。这种协同作用是由两个 GD2 特异性因子驱动的，它们重新调整了巨噬细胞活性的平衡。 GD2 在肿瘤细胞上的连接 (a) 导致表面钙网蛋白上调，这是一种促吞噬细胞的“吃我”信号，可启动细胞进行清除；(b) 中断 GD2 与其新鉴定的配体（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内额外的促吞噬细胞和抗吞噬细胞信号的单克隆抗体联合使用将是最有效的。