Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma
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.
Authors
- Renée Whan (ORCID: https://orcid.org/0000-0002-6664-6344)
- Fabio Luciani (ORCID: https://orcid.org/0000-0003-0666-6324)
- Giuseppe Cirillo (ORCID: https://orcid.org/0000-0002-9592-1333)
- Daniel Catchpoole (ORCID: https://orcid.org/0000-0001-5836-1413)
- Aysen Yuksel (ORCID: https://orcid.org/0000-0002-5101-3536)
- Holger N. Lode (ORCID: https://orcid.org/0000-0002-1201-208X)
- Delia J. Nelson (ORCID: https://orcid.org/0000-0002-8698-5300)
- Tyler Shai-Hee (ORCID: https://orcid.org/0000-0001-5442-4384)
- Toby N. Trahair (ORCID: https://orcid.org/0000-0002-3295-228X)
- Arutha Kulasinghe (ORCID: https://orcid.org/0000-0003-3224-7350)
- Juliet C. Gray (ORCID: https://orcid.org/0000-0002-5652-4722)
- Tatyana Chtanova (ORCID: https://orcid.org/0000-0003-3419-4483)
- Francis Lin (ORCID: https://orcid.org/0000-0001-6913-2245)
- Daniele Mercatelli (ORCID: https://orcid.org/0000-0003-3228-0580)
- Colin R. McHenry (ORCID: https://orcid.org/0000-0001-5721-1149)
- Maria Kasherman (ORCID: https://orcid.org/0000-0003-0169-7578)
- Jessica L. Bell (ORCID: https://orcid.org/0000-0002-8875-0943)
- Riccardo Cazzoli (ORCID: https://orcid.org/0000-0003-2813-3510)
- Toni Rose Jue (ORCID: https://orcid.org/0000-0002-8449-5973)
- Jonathan Chee (ORCID: https://orcid.org/0000-0002-7986-2708)
- Chelsea Mayoh (ORCID: https://orcid.org/0000-0002-6398-3046)
- Vu Pham (ORCID: https://orcid.org/0000-0002-8884-3584)
- Blake J. Cochran (ORCID: https://orcid.org/0000-0002-9615-7939)
- Emanuele Valli (ORCID: https://orcid.org/0000-0002-0928-8624)
- Nicodemus Tedla (ORCID: https://orcid.org/0000-0002-8226-8064)
- Orazio Vittorio (ORCID: https://orcid.org/0000-0002-6610-1889)
- Kris Stevens
- Michelle Haber (ORCID: https://orcid.org/0000-0003-2036-8817)
- Maté Biro (ORCID: https://orcid.org/0000-0001-5852-3726)
- Iveta Šlapetová
- Federica Saletta (ORCID: https://orcid.org/0000-0003-0598-3504)
- Jayne Murray (ORCID: https://orcid.org/0000-0002-1861-6570)
- Jourdin R.C. Rouaen (ORCID: https://orcid.org/0000-0002-6206-9463)
- Antonietta Salerno (ORCID: https://orcid.org/0009-0003-3927-2302)
- Ensieh Poursani (ORCID: https://orcid.org/0000-0001-7566-9831)
- Naomi Damstra
- Feyza Colakoglu Veli
- Giulia Castrogiovanni
Institutions
- Garvan Institute of Medical Research (AU)
- The University of Queensland (AU)
- The University of Western Australia (AU)
- Curtin University (AU)
- Universitätsmedizin Greifswald (DE)
- Cancer Institute of New South Wales (AU)
- Children's Hospital at Westmead (AU)
- UNSW Sydney (AU)
- EMBL Australia (AU)
- The George Institute for Global Health (AU)
- Children's Cancer Institute Australia (AU)
- Sydney Children's Hospital (AU)
- Institute for Respiratory Health (AU)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Southampton (GB)
- University of Calabria (IT)
- European Institute of Oncology (IT)
- University of Bologna (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-12
- DOI
- https://doi.org/10.1038/s41467-024-54689-x
- Citations
- 7
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.58
Funders
- Cancer Australia
- Cure Cancer Australia Foundation
- University of New South Wales
- icare
- Medical Research Council
- National Health and Medical Research Council
- Cancer Council Western Australia