Glycolipid-Loaded Nanoparticles Harness Inkt Cells For Tumor Immunotherapy

Abstract Invariant natural killer T cells (iNKT) have a well-documented role in anti-tumor immunity through their release of proinflammatory cytokines and cytotoxic compounds. As iNKT cells can have direct and indirect killing effects on tumor cells, we propose a novel strategy for activating iNKT cells, via a PLGA nanoparticle delivery platform, to promote anti-tumor immune responses. Poly-lactic-co-glycolic acid (PLGA) nanoparticles can be reproducibly loaded with an iNKT cell glycolipid agonist, alpha-galactosylceramide (αGalCer), and a tumor associated antigen, ovalbumin (OVA). These dual-loaded PLGA nanoparticles rapidly activate iNKT cells in vivo to produce IFNgamma. Furthermore, in an in vivo model of melanoma, using B16F10-OVA cells, both prophylactic and therapeutic administration of nanoparticles containing αGalCer and OVA led to decreased tumor cell growth and increased survival. Ongoing studies are extending these concepts to PLGA nanoparticles loaded with αGalCer plus an immunogenic peptide from the naturally expressed melanocyte protein glycoprotein 100, gp100 25-33. This novel delivery system provides a platform with tremendous potential to harness iNKT cells for cancer immunotherapy purposes and as part of combinational therapies with other approaches such as checkpoint inhibitors.