Anti-disialoganglioside (GD2) antibody therapy has provided clinical benefit to patients with neuroblastoma however efficacy is likely impaired by the immunosuppressive tumor microenvironment. We have previously defined a link between intratumoral copper levels and immune evasion. Here, we report that adjuvant copper chelation potentiates anti-GD2 antibody therapy to confer durable tumor control in immunocompetent models of neuroblastoma. Mechanistic studies reveal copper chelation creates an immune-primed tumor microenvironment through enhanced infiltration and activity of Fc-receptor-bearing cells, specifically neutrophils which are emerging as key effectors of antibody therapy. Moreover, we report copper sequestration by neuroblastoma attenuates neutrophil function which can be successfully reversed using copper chelation to increase pro-inflammatory effector functions. Importantly, we repurpose the clinically approved copper chelating agent Cuprior as a non-toxic, efficacious immunomodulatory strategy. Collectively, our findings provide evidence for the clinical testing of Cuprior as an adjuvant to enhance the activity of anti-GD2 antibody therapy and improve outcomes for patients with neuroblastoma.

抗二唾液酸神经节苷脂 （GD2） 抗体疗法为神经母细胞瘤患者提供了临床益处，但免疫抑制性肿瘤微环境可能会损害疗效。我们之前已经定义了瘤内铜水平与免疫逃避之间的联系。在这里，我们报道了辅助铜螯合可增强抗 GD2 抗体治疗，从而在免疫功能正常的神经母细胞瘤模型中提供持久的肿瘤控制。机制研究表明，铜螯合通过增强携带 Fc 受体的细胞的浸润和活性来创造免疫引发的肿瘤微环境，特别是中性粒细胞，它们正在成为抗体治疗的关键效应物。此外，我们报道神经母细胞瘤的铜隔离会减弱中性粒细胞功能，这可以通过铜螯合成功逆转以增加促炎效应器功能。重要的是，我们将临床批准的铜螯合剂 Cuprior 重新用作无毒、有效的免疫调节策略。总的来说，我们的研究结果为 Cuprior 作为辅助治疗以增强抗 GD2 抗体治疗活性并改善神经母细胞瘤患者的预后提供了临床测试证据。