A Novel Treatment for Ocular Tumors Using Membrane FasL Vesicles to Activate Innate Immunity and Terminate Immune Privilege

Abstract

Ocular immune privilege promotes tumor growth by hindering the development of innate and adaptive immunity. A prior study showed that ocular tumors expressing the membrane-only form of Fas ligand (FasL) terminate immune privilege, induce vigorous inflammation, undergo rejection, and induce systemic protective immunity. In these previous experiments the tumor cells used were genetically engineered to express membrane FasL. As an initial step toward developing an immunotherapy for intraocular tumors, the present study was conducted to examine whether injection of microvesicles expressing membrane FasL into ocular tumors (that are FasL negative) would have a similar effect. Microvesicles expressing either no FasL or membrane-only Fas ligand were coinjected with L5178Y-R lymphoma cells into the anterior chambers (AC) of DBA/2 mice. Tumor cells coinjected with control vesicles grew progressively in the AC, and all mice died of metastatic disease by day 15. By contrast, a single injection of membrane FasL vesicles induced a potent inflammatory response characterized by GR1+ neutrophils and F4/80+ macrophages and significantly improved survival from 0% in untreated mice to 58% in mFasL-treated mice. Among the surviving mice, the ocular tumor was eliminated in 55%, and the mice exhibited systemic protection from a second tumor challenge. In the remaining 45%, the ocular tumor was not eliminated, but the mice were protected from liver metastases. Bioactive membrane FasL microvesicles coinjected with tumor cells induce a potent inflammatory response that terminates immune privilege, eliminates ocular tumors, and prevents metastatic disease.