title: CD1d-antibody fusion proteins target iNKT cells to the tumor and trigger long-term therapeutic responses.
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.
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, 1066, Epalinges, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Corgnac
authors.forename: Rachel
authors.initials: R
authors.lastname: Perret
authors.forename: Laurent
authors.initials: L
authors.lastname: Derré
authors.forename: Lianjun
authors.initials: L
authors.lastname: Zhang
authors.forename: Kathrin
authors.initials: K
authors.lastname: Stirnemann
authors.forename: Maurice
authors.initials: M
authors.lastname: Zauderer
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Mach
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Alena
authors.initials: A
authors.lastname: Donda
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D005699:Galactosylceramides / Q000276:immunology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology / Q000494:pharmacology*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology*
chemical_list: D055610:Antigens, CD1d; C526877:CD1D protein, human; D005699:Galactosylceramides; D007128:Immunoglobulin Fragments; D011993:Recombinant Fusion Proteins; C493154:alpha-galactosylceramide