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2024

Nat Commun. 2024 Dec 12;15(1):10462. doi: 10.1038/s41467-024-54689-x.

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 Cazzol, 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, Orazio Vittorio

School of Biomedical Sciences, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia. Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia. Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, Italy. Institute for Respiratory Health, National Centre for Asbestos Related Diseases, University of Western Australia, Perth, WA, Australia. Curtin Medical School, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia. Curtin Health Innovation Research Institute, Bentley, WA, Australia. Katharina Gaus Light Microscopy Facility, University of New South Wales, Sydney, NSW, Australia. School of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW Sydney, Sydney, NSW, Australia. EMBL Australia, Single Molecule Science Node, School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia. Tumour Bank, Children's Hospital at Westmead, Westmead, NSW, Australia. Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy. Garvan Institute of Medical Research, Sydney, NSW, Australia. Frazer Institute, University of Queensland, Brisbane, QLD, Australia. Department of Pharmacy Health and Nutritional Science, University of Calabria, Rende, Italy. Department of Pediatric Hematology-Oncology, University Medicine Greifswald, Greifswald, Germany. Kirby Institute for Infection and Immunity, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia. Centre for Cancer Immunology, University of Southampton, Southampton, UK. Kids Cancer Centre, Sydney Children's Hospital, Sydney, NSW, Australia.

Service type: Stock strains

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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