Impairing temozolomide resistance driven by glioma stem‐like cells with adjuvant immunotherapy targeting O‐acetyl GD2 ganglioside

• Published in: International journal of cancer 2020-01, Vol.146 (2), p.424-438
• Main Authors: Fleurence, Julien, Bahri, Meriem, Fougeray, Sophie, Faraj, Sébastien, Vermeulen, Sarah, Pinault, Emilie, Geraldo, Fanny, Oliver, Lisa, Véziers, Joëlle, Marquet, Pierre, Rabé, Marion, Gratas, Catherine, Vallette, François, Pecqueur, Claire, Paris, François, Birklé, Stéphane
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - pharmacology; Adjuvants, Immunologic - therapeutic use; Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Brain cancer; Cancer; cancer immunotherapy; Cell death; Cell Line, Tumor; Cell Self Renewal - drug effects; Cell Self Renewal - immunology; Cell self-renewal; Chemoresistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - immunology; Drug Synergism; Gangliosides - antagonists & inhibitors; Gangliosides - immunology; Genotoxicity; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - immunology; Glioblastoma - pathology; Glioblastoma cells; Glioma; Glioma cells; Humans; Immunotherapy; Medical research; Mice; Monoclonal antibodies; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - immunology; Nestin; oncology; Reagents; Stem cells; Temozolomide; Temozolomide - pharmacology; Temozolomide - therapeutic use; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32533

Stem cell chemoresistance remains challenging the efficacy of the front‐line temozolomide against glioblastoma. Novel therapies are urgently needed to fight those cells in order to control tumor relapse. Here, we report that anti‐O‐acetyl‐GD2 adjuvant immunotherapy controls glioma stem‐like cell‐driven chemoresistance. Using patient‐derived glioblastoma cells, we found that glioma stem‐like cells overexpressed O‐acetyl‐GD2. As a result, monoclonal antibody 8B6 immunotherapy significantly increased temozolomide genotoxicity and tumor cell death in vitro by enhancing temozolomide tumor uptake. Furthermore, the combination therapy decreased the expression of the glioma stem‐like cell markers CD133 and Nestin and compromised glioma stem‐like cell self‐renewal capabilities. When tested in vivo, adjuvant 8B6 immunotherapy prevented the extension of the temozolomide‐resistant glioma stem‐like cell pool within the tumor bulk in vivo and was more effective than the single agent therapies. This is the first report demonstrating that anti‐O‐acetyl‐GD2 monoclonal antibody 8B6 targets glioblastoma in a manner that control temozolomide‐resistance driven by glioma stem‐like cells. Together our results offer a proof of concept for using anti‐O‐acetyl GD2 reagents in glioblastoma to develop more efficient combination therapies for malignant gliomas. What's new? Glioblastoma multiforme (GBM) is a complex malignancy harboring differentiated tumor‐bulk cells and self‐renewing GBM stem‐like cells (GSCs). Targeting both cell compartments is necessary to improve prognosis. Here, the authors characterize OAcGD2 ganglioside as a novel GSCs marker that sensitizes chemo‐resistant GSCs to TMZ. The combination of anti‐OAcGD2 monoclonal antibody 8B6 with TMZ results in increased temozolomide genotoxicity and tumor cell death in vitro by enhancing temozolomide tumor uptake. Furthermore, 8B6 works synergistically with TMZ to compromise GSCs self‐renewal. The identification of OAcGD2 as a GSC‐associated antigen offers a novel opportunity for optimizing TMZ chemotherapy in GBM patients to prevent recurrence.