CD1d-antibody fusion proteins target iNKT cells to the tumor and trigger long-term therapeutic responses.

Détails

Ressource 1Télécharger: BIB_ED058D025B50.P001.pdf (551.81 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_ED058D025B50
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
CD1d-antibody fusion proteins target iNKT cells to the tumor and trigger long-term therapeutic responses.
Périodique
Cancer Immunology, Immunotherapy
Auteur(s)
Corgnac S., Perret R., Derré L., Zhang L., Stirnemann K., Zauderer M., Speiser D.E., Mach J.P., Romero P., Donda A.
ISSN
1432-0851 (Electronic)
ISSN-L
0340-7004
Statut éditorial
Publié
Date de publication
2013
Volume
62
Numéro
4
Pages
747-760
Langue
anglais
Résumé
Despite the well-established antitumor activity of CD1d-restricted invariant natural killer T lymphocytes (iNKT), their use for cancer therapy has remained challenging. This appears to be due to their strong but short-lived activation followed by long-term anergy after a single administration of the CD1d agonist ligand alpha-galactosylceramide (αGC). As a promising alternative, we obtained sustained mouse iNKT cell responses associated with prolonged antitumor effects through repeated administrations of tumor-targeted recombinant sCD1d-antitumor scFv fusion proteins loaded with αGC. Here, we demonstrate that CD1d fusion proteins bound to tumor cells via the antibody fragment specific for a tumor-associated antigen, efficiently activate human iNKT cell lines leading to potent tumor cell lysis. The importance of CD1d tumor targeting was confirmed in tumor-bearing mice in which only the specific tumor-targeted CD1d fusion protein resulted in tumor inhibition of well-established aggressive tumor grafts. The therapeutic efficacy correlated with the repeated activation of iNKT and natural killer cells marked by their release of TH1 cytokines, despite the up-regulation of the co-inhibitory receptor PD-1. Our results demonstrate the superiority of providing the superagonist αGC loaded on recombinant CD1d proteins and support the use of αGC/sCD1d-antitumor fusion proteins to secure a sustained human and mouse iNKT cell activation, while targeting their cytotoxic activity and cytokine release to the tumor site.
Mots-clé
Cancer immunotherapy, iNKT cells, CD1d, Tumor targeting, Fusion protein
Pubmed
Web of science
Création de la notice
16/05/2013 7:15
Dernière modification de la notice
20/08/2019 16:14
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