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 (alpha-GalCer), and a model 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 alpha-GalCer and OVA led to decreased tumor cell growth and increased survival. We also show our nanoparticle therapy has synergistic potential with two immune checkpoint blockade therapies, anti-PD-1 and anti-CTLA-4, currently used in the clinic for human cancer patients. This novel delivery system provides a platform with tremendous potential to harness iNKT cells for cancer immunotherapy purposes against many different cancer types.