Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma
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...
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54689-x |
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| author | 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 Orazio Vittorio |
| author_facet | 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 Orazio Vittorio |
| author_sort | Jourdin R. C. Rouaen |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-c429ada101b14a66a6b9deabd0facbd0 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c429ada101b14a66a6b9deabd0facbd02024-12-15T12:10:03ZengNature PortfolioNature Communications2041-17232024-12-0115112010.1038/s41467-024-54689-xCopper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastomaJourdin R. C. Rouaen0Antonietta Salerno1Tyler Shai-Hee2Jayne E. Murray3Giulia Castrogiovanni4Charlotte McHenry5Toni Rose Jue6Vu Pham7Jessica Lilian Bell8Ensieh Poursani9Emanuele Valli10Riccardo Cazzoli11Naomi Damstra12Delia J. Nelson13Kofi L. P. Stevens14Jonathan Chee15Iveta Slapetova16Maria Kasherman17Renee Whan18Francis Lin19Blake J. Cochran20Nicodemus Tedla21Feyza Colakoglu Veli22Aysen Yuksel23Chelsea Mayoh24Federica Saletta25Daniele Mercatelli26Tatyana Chtanova27Arutha Kulasinghe28Daniel Catchpoole29Giuseppe Cirillo30Maté Biro31Holger N. Lode32Fabio Luciani33Michelle Haber34Juliet C. Gray35Toby N. Trahair36Orazio Vittorio37School of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneyChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneyDepartment of Experimental Oncology, IEO, European Institute of Oncology IRCCSChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW SydneyInstitute for Respiratory Health, National Centre for Asbestos Related Diseases, University of Western AustraliaCurtin Medical School, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin UniversityInstitute for Respiratory Health, National Centre for Asbestos Related Diseases, University of Western AustraliaInstitute for Respiratory Health, National Centre for Asbestos Related Diseases, University of Western AustraliaKatharina Gaus Light Microscopy Facility, University of New South WalesKatharina Gaus Light Microscopy Facility, University of New South WalesKatharina Gaus Light Microscopy Facility, University of New South WalesSchool of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneyEMBL Australia, Single Molecule Science Node, School of Biomedical Sciences, UNSW Sydney Tumour Bank, Children’s Hospital at WestmeadSchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneyChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSW SydneyDepartment of Pharmacy and Biotechnology, University of BolognaSchool of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW SydneyFrazer Institute, University of Queensland Tumour Bank, Children’s Hospital at WestmeadDepartment of Pharmacy Health and Nutritional Science, University of CalabriaEMBL Australia, Single Molecule Science Node, School of Biomedical Sciences, UNSW SydneyDepartment of Pediatric Hematology-Oncology, University Medicine GreifswaldSchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneyCentre for Cancer Immunology, University of SouthamptonSchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneySchool of Biomedical Sciences, UNSW Medicine & Health, UNSW SydneyAbstract 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.https://doi.org/10.1038/s41467-024-54689-x |
| spellingShingle | 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 Orazio Vittorio Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma Nature Communications |
| title | Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma |
| title_full | Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma |
| title_fullStr | Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma |
| title_full_unstemmed | Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma |
| title_short | Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma |
| title_sort | copper chelation redirects neutrophil function to enhance anti gd2 antibody therapy in neuroblastoma |
| url | https://doi.org/10.1038/s41467-024-54689-x |
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