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
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