Human Dendritic Cells Derived From Embryonic Stem Cells Stably Modified With CD1d Efficiently Stimulate Antitumor Invariant Natural Killer T Cell Response

Abstract

Invariant natural killer T (iNKT) cells are a unique lymphocyte subpopulation that mediates antitumor activities uponactivation.Acurrent strategy to harness iNKT cells for cancer treatment isendogenous iNKT cell activation using patient-derived dendritic cells (DCs).However,the limitednumberandfunc- tional defects of patient DCs are still the major challenges for this therapeutic approach. In this study, we investigated whether human embryonic stem cells (hESCs) with an ectopically expressed CD1d gene could be exploited to address this issue. Using a lentivector carrying an optimized expression cassette,wegenerated stably modified hESC lines that consistently overexpressed CD1d. These mod- ifiedhESClineswereable to differentiate intoDCsas efficiently as the parental line.Mostimportantly, more than50%of such derived DCs were CD1d+. These CD1d-overexpressing DCs weremore efficient in inducing iNKT cell response than those without modification, and their ability was comparable to that of DCs generated from monocytes of healthy donors. The iNKT cells expanded by the CD1d- overexpressingDCswerefunctional, as demonstratedbytheir ability to lyseiNKTcell-sensitive glioma cells. Therefore, hESCs stably modified with the CD1d genemayserve as a convenient, unlimited, and competent DCsource for iNKT cell-based cancer immunotherapy.