Impairing Temozolomide Resistance Driven by Glioma Stem-like Cells with adjuvant Immunotherapy Targeting O-acetyl GD2 Ganglioside

Julien Fleurence; Meriem Bahri; Sophie Fougeray; Sébastien Faraj; Sarah Vermeulen; Émilie Pinault; Fanny Geraldo; Lisa Oliver; Joëlle Véziers; Pierre Marquet; Marion Rabé; Catherine Gratas; François Vallette; Claire Pecqueur; François Paris; Stéphane Birklé

Impairing Temozolomide Resistance Driven by Glioma Stem-like Cells with adjuvant Immunotherapy Targeting O-acetyl GD2 Ganglioside: A novel synergistic option for glioblastoma therapy

Julien Fleurence ¹ Meriem Bahri ¹ Sophie Fougeray ^{1, 2} Sébastien Faraj ³ Sarah Vermeulen ³ Émilie Pinault ⁴ Fanny Geraldo ⁵ Lisa Oliver ⁵ Joëlle Véziers ^{6, 7, 8} Pierre Marquet ⁹ Marion Rabé ⁵ Catherine Gratas ⁵ François Vallette ^{5, 10} Claire Pecqueur ¹ François Paris ^{1, 10} Stéphane Birklé ^{1, 2, *}

* Corresponding author

1 CRCINA - Département ONCO - Equipe 14 - Endothelium radiobiology and targeting

CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers

2 Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques

3 CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers

4 BISCEm - Biologie Intégrative Santé Chimie Environnement

GEIST - Institut Génomique, Environnement, Immunité, Santé, Thérapeutique

5 CRCINA - Département ONCO - Equipe 9 - Apoptosis and tumor progression -ATP

CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers

6 RMeS - Regenerative Medicine and Skeleton research lab

7 P2R - INSERM UMS016/CNRS UMS3556/UN FED4203 - Plateforme "Production de protéines recombinantes"

SFR François Bonamy - Structure fédérative de recherche François Bonamy

8 Pôle hospitalo-universitaire PHU4 - OTONN - Ostéo-articulaire - Tête et cou - Odontologie - Neurochirurgie - Neurotraumatologie [CHU Nantes]

9 IPPRITT - Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation

10 LabCT - Laboratoire de Biologie des Cancers et de Théranostic [St Herblain, Nantes]

Abstract : Stem cell chemo-resistance is still 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 chemo-resistance. Using patient-derived glioblastoma cells we found that glioma stem-like cells over-expressed 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. This article is protected by copyright. All rights reserved.

Keywords : brain cancer cancer immunotherapy oncology

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Cancer

Complete list of metadatas

Cited literature [75 references] Display Hide Download

https://www.hal.inserm.fr/inserm-02168202
Contributor : Elizabeth Bernardo <>
Submitted on : Friday, June 28, 2019 - 2:56:21 PM
Last modification on : Thursday, July 11, 2019 - 11:11:58 AM

Impairing Temozolomide Resistance Driven by Glioma Stem-like Cells with adjuvant Immunotherapy Targeting O-acetyl GD2 Ganglioside: A novel synergistic option for glioblastoma therapy

File

Restricted access

Identifiers

Collections

Citation

Export

Metrics

67

Contact

Impairing Temozolomide Resistance Driven by Glioma Stem-like Cells with adjuvant Immunotherapy Targeting O-acetyl GD2 Ganglioside: A novel synergistic option for glioblastoma therapy

File

Restricted access

Identifiers

Collections

Citation

Export

Share

Metrics

67

Contact