G-CSF as a suitable alternative to GM-CSF to boost dinutuximab-mediated neutrophil cytotoxicity in neuroblastoma treatment
Autor: | Martinez Sanz, Paula, van Rees, Dieke J, van Zogchel, Lieke M J, Klein, Bart, Bouti, Panagiota, Olsman, Hugo, Schornagel, Karin, Kok, Ivana, Sunak, Ali, Leeuwenburg, Kira, Timmerman, Ilse, Dierselhuis, Miranda P, Kholosy, Waleed M, Molenaar, Jan J, van Bruggen, Robin, van den Berg, Timo K, Kuijpers, Taco W, Matlung, Hanke L, Tytgat, Godelieve A M, Franke, Katka, Afd Pharmaceutics, Pharmaceutics |
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Přispěvatelé: | Afd Pharmaceutics, Pharmaceutics, AII - Cancer immunology, CCA - Cancer biology and immunology, Paediatric Infectious Diseases / Rheumatology / Immunology, AR&D - Amsterdam Reproduction & Development, Paediatric Oncology |
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment Cell Proliferation/drug effects 0302 clinical medicine Adjuvants Immunologic/pharmacology Receptors Tumor Microenvironment Immunology and Allergy Cytotoxicity Immunologic/drug effects Trogocytosis/drug effects immunologic RC254-282 Antibody-dependent cell-mediated cytotoxicity Tumor biology Dinutuximab Neoplasms. Tumors. Oncology. Including cancer and carcinogens Antineoplastic Agents Immunological/pharmacology Immunologic/pharmacology Cytokine Oncology Integrin alpha M Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology 030220 oncology & carcinogenesis Neutrophils/drug effects Molecular Medicine cytotoxicity CD11b Antigen/metabolism immunotherapy Granulocyte Colony-Stimulating Factor/pharmacology Immunologic/drug effects Trogocytosis Immunology Antineoplastic Agents Antineoplastic Combined Chemotherapy Protocols/pharmacology Antibodies Cell Line 03 medical and health sciences neuroblastoma In vivo Neuroblastoma Cell Line Tumor medicine CD18 Antigens/metabolism innate Humans Neuroblastoma/drug therapy Adjuvants Pharmacology business.industry IgG/metabolism Basic Tumor Immunology Immunotherapy Receptors IgG/metabolism medicine.disease immunity Antibodies Monoclonal/pharmacology Coculture Techniques cytokines Monoclonal/pharmacology 030104 developmental biology Cancer research biology.protein Immunological/pharmacology business |
Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss 5 (2021) Journal for ImmunoTherapy of Cancer, 9(5), 1. BioMed Central Ltd. Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, 9(5), 1. BioMed Central Journal for immunotherapy of cancer, 9(5):e002259. BioMed Central Ltd. |
ISSN: | 2051-1426 |
DOI: | 10.1136/jitc-2020-002259 |
Popis: | BackgroundCurrent immunotherapy for patients with high-risk neuroblastoma involves the therapeutic antibody dinutuximab that targets GD2, a ganglioside expressed on the majority of neuroblastoma tumors. Opsonized tumor cells are killed through antibody-dependent cellular cytotoxicity (ADCC), a process mediated by various immune cells, including neutrophils. The capacity of neutrophils to kill dinutuximab-opsonized tumor cells can be further enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been shown in the past to improve responses to anti-GD2 immunotherapy. However, access to GM-CSF (sargramostim) is limited outside of Northern America, creating a high clinical need for an alternative method to stimulate dinutuximab responsiveness in the treatment of neuroblastoma. In this in vitro study, we have investigated whether clinically well-established granulocyte colony-stimulating factor (G-CSF) can be a potentially suitable alternative for GM-CSF in the dinutuximab immunotherapy regimen of patients with neuroblastoma.MethodsWe compared the capacity of neutrophils stimulated either in vitro or in vivo with GM-CSF or G-CSF to kill dinutuximab-opsonized GD2-positive neuroblastoma cell lines and primary patient tumor material. Blocking experiments with antibodies inhibiting either respective Fc gamma receptors (FcγR) or neutrophil integrin CD11b/CD18 demonstrated the involvement of these receptors in the process of ADCC. Flow cytometry and live cell microscopy were used to quantify and visualize neutrophil-neuroblastoma interactions.ResultsWe found that G-CSF was as potent as GM-CSF in enhancing the killing capacity of neutrophils towards neuroblastoma cells. This was observed with in vitro stimulated neutrophils, and with in vivo stimulated neutrophils from both patients with neuroblastoma and healthy donors. Enhanced killing due to GM-CSF or G-CSF stimulation was consistent regardless of dinutuximab concentration, tumor-to-neutrophil ratio and concentration of the stimulating cytokine. Both GM-CSF and G-CSF stimulated neutrophils required FcγRIIa and CD11b/CD18 integrin to perform ADCC, and this was accompanied by trogocytosis of tumor material by neutrophils and tumor cell death in both stimulation conditions.ConclusionsOur preclinical data support the use of G-CSF as an alternative stimulating cytokine to GM-CSF in the treatment of high-risk neuroblastoma with dinutuximab, warranting further testing of G-CSF in a clinical setting. |
Databáze: | OpenAIRE |
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