Cd47-sirpα checkpoint inhibition enhances neutrophil-mediated killing of dinutuximab-opsonized neuroblastoma cells

Paula Martínez-Sanz, Arjan J. Hoogendijk, Paul J. J. H. Verkuijlen, Karin Schornagel, Robin van Bruggen, Timo K. van den Berg, Godelieve A. M. Tytgat, Katka Franke, Taco W. Kuijpers, Hanke L. Matlung

Research output: Contribution to journalArticle*Academicpeer-review

Abstract

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.
Original languageEnglish
Article number4261
JournalCancers
Volume13
Issue number17
DOIs
Publication statusPublished - 1 Sep 2021

Keywords

  • Antibody therapy
  • Antibody-dependent cellular cytotoxicity
  • CD47-SIRPα
  • Checkpoint blockade
  • Dinutuximab
  • Immunotherapy
  • Neuroblastoma
  • Neutrophils

Cite this