Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma.

Rouaen, JRC; Salerno, A; Shai-Hee, T; Murray, JE; Castrogiovanni, G; McHenry, C; Jue, TR; Pham, V; Bell, JL; Poursani, E; Valli, E; Cazzoli, R; Damstra, N; Nelson, DJ; Stevens, KLP; Chee, J; Slapetova, I; Kasherman, M; Whan, R; Lin, F; Cochran, BJ; Tedla, N; Veli, FC; Yuksel, A; Mayoh, C; Saletta, F; Mercatelli, D; Chtanova, T; Kulasinghe, A; Catchpoole, D; Cirillo, G; Biro, M; Lode, HN; Luciani, F; Haber, M; Gray, JC; Trahair, TN; Vittorio, O

Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma.

Rouaen, JRC Salerno, A Shai-Hee, T Murray, JE Castrogiovanni, G McHenry, C Jue, TR Pham, V Bell, JL Poursani, E Valli, E Cazzoli, R Damstra, N Nelson, DJ Stevens, KLP Chee, J Slapetova, I Kasherman, M Whan, R Lin, F Cochran, BJ Tedla, N Veli, FC Yuksel, A Mayoh, C Saletta, F Mercatelli, D Chtanova, T Kulasinghe, A Catchpoole, D

Cirillo, G Biro, M Lode, HN Luciani, F Haber, M Gray, JC Trahair, TN Vittorio, O

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Publisher:: NATURE PORTFOLIO
Publication Type:: Journal Article
Citation:: Nat Commun, 2024, 15, (1), pp. 10462
Issue Date:: 2024-12-12

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Field	Value	Language
dc.contributor.author	Rouaen, JRC
dc.contributor.author	Salerno, A
dc.contributor.author	Shai-Hee, T
dc.contributor.author	Murray, JE
dc.contributor.author	Castrogiovanni, G
dc.contributor.author	McHenry, C
dc.contributor.author	Jue, TR
dc.contributor.author	Pham, V
dc.contributor.author	Bell, JL
dc.contributor.author	Poursani, E
dc.contributor.author	Valli, E
dc.contributor.author	Cazzoli, R
dc.contributor.author	Damstra, N
dc.contributor.author	Nelson, DJ
dc.contributor.author	Stevens, KLP
dc.contributor.author	Chee, J
dc.contributor.author	Slapetova, I
dc.contributor.author	Kasherman, M
dc.contributor.author	Whan, R
dc.contributor.author	Lin, F
dc.contributor.author	Cochran, BJ
dc.contributor.author	Tedla, N
dc.contributor.author	Veli, FC
dc.contributor.author	Yuksel, A
dc.contributor.author	Mayoh, C
dc.contributor.author	Saletta, F
dc.contributor.author	Mercatelli, D
dc.contributor.author	Chtanova, T
dc.contributor.author	Kulasinghe, A
dc.contributor.author	Catchpoole, D https://orcid.org/0000-0001-5836-1413
dc.contributor.author	Cirillo, G
dc.contributor.author	Biro, M
dc.contributor.author	Lode, HN
dc.contributor.author	Luciani, F
dc.contributor.author	Haber, M
dc.contributor.author	Gray, JC
dc.contributor.author	Trahair, TN
dc.contributor.author	Vittorio, O
dc.date.accessioned	2025-03-19T03:44:06Z
dc.date.available	2024-11-19
dc.date.available	2025-03-19T03:44:06Z
dc.date.issued	2024-12-12
dc.identifier.citation	Nat Commun, 2024, 15, (1), pp. 10462
dc.identifier.issn	2041-1723
dc.identifier.issn	2041-1723
dc.identifier.uri	http://hdl.handle.net/10453/185988
dc.description.abstract	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.
dc.format	Electronic
dc.language	eng
dc.publisher	NATURE PORTFOLIO
dc.relation.ispartof	Nat Commun
dc.relation.isbasedon	10.1038/s41467-024-54689-x
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Animals
dc.subject.mesh	Neutrophils
dc.subject.mesh	Humans
dc.subject.mesh	Copper
dc.subject.mesh	Gangliosides
dc.subject.mesh	Chelating Agents
dc.subject.mesh	Mice
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Tumor Microenvironment
dc.subject.mesh	Female
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Neutrophils
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Copper
dc.subject.mesh	Gangliosides
dc.subject.mesh	Chelating Agents
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Female
dc.subject.mesh	Tumor Microenvironment
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Animals
dc.subject.mesh	Neutrophils
dc.subject.mesh	Humans
dc.subject.mesh	Copper
dc.subject.mesh	Gangliosides
dc.subject.mesh	Chelating Agents
dc.subject.mesh	Mice
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Tumor Microenvironment
dc.subject.mesh	Female
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.title	Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma.
dc.type	Journal Article
utslib.citation.volume	15
utslib.location.activity	England
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Computer Science
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Artificial Intelligence Institute (AAII)
pubs.organisational-group	University of Technology Sydney/UTS Groups/INSIGHT: Institute for Innovative Solutions for Well-being and Health/Digital, Virtual and AI in Health Collaborative (DVAIHC)
pubs.organisational-group	University of Technology Sydney/UTS Groups/INSIGHT: Institute for Innovative Solutions for Well-being and Health
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Artificial Intelligence Institute (AAII)/Australian Artificial Intelligence Institute (AAII) Associate Members
pubs.organisational-group	University of Technology Sydney/UTS Groups/The Trustworthy Digital Society
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2025-03-19T03:44:02Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	15
utslib.citation.issue	1

Abstract:

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.

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http://hdl.handle.net/10453/185988