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TY - JOUR

T1 - Cd47-sirpα checkpoint inhibition enhances neutrophil-mediated killing of dinutuximab-opsonized neuroblastoma cells

AU - Martínez-Sanz, Paula

AU - Hoogendijk, Arjan J.

AU - Verkuijlen, Paul J. J. H.

AU - Schornagel, Karin

AU - van Bruggen, Robin

AU - van den Berg, Timo K.

AU - Tytgat, Godelieve A. M.

AU - Franke, Katka

AU - Kuijpers, Taco W.

AU - Matlung, Hanke L.

N1 - Funding Information: Funding: This research was funded by the Dutch Cancer Society, grant #11537. Publisher Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland.

PY - 2021/9/1

Y1 - 2021/9/1

N2 - 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.

AB - 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.

KW - Antibody therapy

KW - Antibody-dependent cellular cytotoxicity

KW - CD47-SIRPα

KW - Checkpoint blockade

KW - Dinutuximab

KW - Immunotherapy

KW - Neuroblastoma

KW - Neutrophils

UR - http://www.scopus.com/inward/record.url?scp=85120887859&partnerID=8YFLogxK

U2 - 10.3390/cancers13174261

DO - 10.3390/cancers13174261

M3 - Article

C2 - 34503071

VL - 13

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 17

M1 - 4261

ER -