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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-012-1381-7) contains supplementary material, which is available to authorized users.
Highlights
Human Va24-invariant natural killer T lymphocytes, and their murine counterparts Va14-iNKT cells, represent a particular sublineage of T lymphocytes activated by self- and microbial-derived glycolipids in the context of the monomorphic MHC-related molecule CD1d
The present study demonstrates the therapeutic efficacy of recombinant soluble part of mouse CD1d (sCD1d)-antitumor scFv fusion proteins via the sustained activation of murine and human cytolytic iNKT cells
Recombinant CD1d proteins have the capacity to keep iNKT cells reactive through multiple stimulations, in contrast to their unresponsiveness after repeated challenge by aGC-loaded antigen-presenting cells (APCs)
Summary
Human Va24-invariant natural killer T lymphocytes (iNKT), and their murine counterparts Va14-iNKT cells, represent a particular sublineage of T lymphocytes activated by self- and microbial-derived glycolipids in the context of the monomorphic MHC-related molecule CD1d Their importance in the transactivation of innate and adaptive immune responses has been extensively described [1, 2], as well as their protective or pathological role in various conditions [3]. We have instead showed that sustained mouse iNKT cell responses could be induced by repeated stimulations with recombinant aGC-loaded sCD1d fusion proteins [19] This prolonged responsiveness of iNKT cells resulted in potent antitumor activity when CD1d was targeted to the tumor site by its fusion to an anti-HER2 antitumor antibody fragment [19]. The importance of CD1d tumor targeting to promote sustained activation of iNKT cells and prolonged tumor inhibition is further characterized in mice in therapeutic settings
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