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

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Version: Final published version
Serval ID
serval:BIB_ED058D025B50
Type
Article: article from journal or magazin.
Collection
Publications
Title
CD1d-antibody fusion proteins target iNKT cells to the tumor and trigger long-term therapeutic responses.
Journal
Cancer Immunology, Immunotherapy
Author(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
Publication state
Published
Issued date
2013
Volume
62
Number
4
Pages
747-760
Language
english
Abstract
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.
Keywords
Cancer immunotherapy, iNKT cells, CD1d, Tumor targeting, Fusion protein
Pubmed
Web of science
Create date
16/05/2013 8:15
Last modification date
20/08/2019 17:14
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