Martínez-Sanz Paula, Hoogendijk Arjan J, Verkuijlen Paul J J H, Schornagel Karin, van Bruggen Robin, van den Berg Timo K, Tytgat Godelieve A M, Franke Katka, Kuijpers Taco W, Matlung Hanke L
Sanquin Research and Landsteiner Laboratory, Department of Molecular Hematology, Amsterdam UMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands.
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
Cancers (Basel). 2021 Aug 24;13(17):4261. doi: 10.3390/cancers13174261.
High-risk neuroblastoma, especially after recurrence, still has a very low survival rate. Immune checkpoint inhibitors targeting T cells have shown remarkable clinical efficacy in adult solid tumors, but their effects in pediatric cancers have been limited so far. On the other hand, targeting myeloid immune checkpoints, such as CD47-SIPRα, provide the opportunity to enhance antitumor effects of myeloid cells, including that of neutrophils, especially in the presence of cancer-opsonizing antibodies. Disialoganglioside (GD2)-expressing neuroblastoma cells targeted with anti-GD2 antibody dinutuximab are in part eradicated by neutrophils, as they recognize and bind the antibody targeted tumor cells through their Fc receptors. Therapeutic targeting of the innate immune checkpoint CD47-SIRPα has been shown to promote the potential of neutrophils as cytotoxic cells in different solid tumor indications using different cancer-targeting antibodies. Here, we demonstrate that the capacity of neutrophils to kill dinutuximab-opsonized neuroblastoma cells is also controlled by the CD47-SIRPα axis and can be further enhanced by antagonizing CD47-SIRPα interactions. In particular, CD47-SIRPa checkpoint inhibition enhanced neutrophil-mediated ADCC of dinutuximab-opsonized adrenergic neuroblastoma cells, whereas mesenchymal neuroblastoma cells may evade immune recognition by a reduction of GD2 expression. These findings provide a rational basis for targeting CD47-SIRPα interactions to potentiate dinutuximab responsiveness in neuroblastomas with adrenergic phenotype.
高危神经母细胞瘤，尤其是复发后，生存率仍然很低。靶向T细胞的免疫检查点抑制剂在成人实体瘤中已显示出显著的临床疗效，但迄今为止它们在儿科癌症中的效果有限。另一方面，靶向髓系免疫检查点，如CD47-SIPRα，为增强髓系细胞（包括中性粒细胞）的抗肿瘤作用提供了机会，尤其是在存在癌症调理抗体的情况下。用抗GD2抗体地努图希单抗靶向的表达双唾液酸神经节苷脂（GD2）的神经母细胞瘤细胞部分被中性粒细胞清除，因为它们通过其Fc受体识别并结合抗体靶向的肿瘤细胞。在不同的实体瘤适应症中，使用不同的癌症靶向抗体，对先天性免疫检查点CD47-SIRPα进行治疗性靶向已显示可促进中性粒细胞作为细胞毒性细胞的潜力。在这里，我们证明中性粒细胞杀死地努图希单抗调理的神经母细胞瘤细胞的能力也受CD47-SIRPα轴的控制，并且可以通过拮抗CD47-SIRPα相互作用进一步增强。特别是，CD47-SIRPa检查点抑制增强了中性粒细胞介导的地努图希单抗调理的嗜铬性神经母细胞瘤细胞的抗体依赖性细胞介导的细胞毒性作用，而间充质神经母细胞瘤细胞可能通过降低GD2表达来逃避免疫识别。这些发现为靶向CD47-SIRPα相互作用以增强地努图希单抗对嗜铬性表型神经母细胞瘤的反应性提供了合理依据。
