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

Jourdin R. C. Rouaen, Antonietta Salerno, Tyler Shai-Hee, Jayne E. Murray, Giulia Castrogiovanni, Charlotte McHenry, Toni Rose Jue, Vu Pham, Jessica Lilian Bell, Ensieh Poursani, Emanuele Valli, Riccardo Cazzoli, Naomi Damstra, Delia J. Nelson, Kofi L. P. Stevens, Jonathan Chee, Iveta Slapetova, Maria Kasherman, Renee Whan, Francis Lin, Blake J. Cochran, Nicodemus Tedla, Feyza Colakoglu Veli, Aysen Yuksel, Chelsea Mayoh, Federica Saletta, Daniele Mercatelli, Tatyana Chtanova, Arutha Kulasinghe, Daniel Catchpoole, Giuseppe Cirillo, Maté Biro, Holger N. Lode, Fabio Luciani, Michelle Haber, Juliet C. Gray, Toby N. Trahair and Orazio Vittorio ()
Additional contact information
Jourdin R. C. Rouaen: UNSW Sydney
Antonietta Salerno: UNSW Sydney
Tyler Shai-Hee: UNSW Sydney
Jayne E. Murray: UNSW Sydney
Giulia Castrogiovanni: UNSW Sydney
Charlotte McHenry: UNSW Sydney
Toni Rose Jue: UNSW Sydney
Vu Pham: UNSW Sydney
Jessica Lilian Bell: UNSW Sydney
Ensieh Poursani: UNSW Sydney
Emanuele Valli: European Institute of Oncology IRCCS
Riccardo Cazzoli: UNSW Sydney
Naomi Damstra: University of Western Australia
Delia J. Nelson: Curtin University
Kofi L. P. Stevens: University of Western Australia
Jonathan Chee: University of Western Australia
Iveta Slapetova: University of New South Wales
Maria Kasherman: University of New South Wales
Renee Whan: University of New South Wales
Francis Lin: UNSW Sydney
Blake J. Cochran: UNSW Sydney
Nicodemus Tedla: UNSW Sydney
Feyza Colakoglu Veli: UNSW Sydney
Aysen Yuksel: Children’s Hospital at Westmead
Chelsea Mayoh: UNSW Sydney
Federica Saletta: UNSW Sydney
Daniele Mercatelli: University of Bologna
Tatyana Chtanova: UNSW Sydney
Arutha Kulasinghe: University of Queensland
Daniel Catchpoole: Children’s Hospital at Westmead
Giuseppe Cirillo: University of Calabria
Maté Biro: UNSW Sydney
Holger N. Lode: University Medicine Greifswald
Fabio Luciani: UNSW Sydney
Michelle Haber: UNSW Sydney
Juliet C. Gray: University of Southampton
Toby N. Trahair: UNSW Sydney
Orazio Vittorio: UNSW Sydney

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54689-x

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