TRAIL-armed exosomes as a novel anti-tumor therapy

Purpose: Exosomes deliver signals to target cells and could thus be exploited as an innovative therapeutic tool. We investigated the ability of membrane TNF-related apoptosis-inducing ligand (TRAIL)-armed exosomes to deliver pro-apoptotic signals to cancer cells and mediate growth inhibition in different tumor models. Experimental Methods and Results: K562 cells, transduced with lentiviral human membrane TRAIL, were used for the production of TRAIL⁺ exosomes, which were studied by Nanosight, cytofluorimetry, immunoelectronmicroscopy, Western blot and ELISA. <i>In vitro</i>, TRAIL⁺ exosomes induced more pronounced apoptosis (detected by Annexin V/propidium iodide and activated Caspase 3) in TRAIL-death receptor (DR)5⁺ cells (SUDHL4 lymphoma and INT12 melanoma), with respect to the DR5^-DR4⁺KMS11 multiple myeloma. Intra-tumor injection of TRAIL⁺ exosomes, but not mock exosomes, induced growth inhibition of SUDHL4 (68%) and INT12 (51%), and necrosis in KMS11 tumors. After rapid blood clearance systemically administered TRAIL⁺ exosomes accumulated in liver, lungs and spleen and homed to tumor site, leading to a significant reduction of tumor growth (58%) in SUDHL4-bearing mice. The treatment of INT12-bearing animals promoted tumor necrosis and a not statistically significant tumor volume reduction. In KMS11-bearing mice, despite massive perivascular necrosis, no significant tumor growth inhibition was detected. Conclusions: TRAIL-armed exosomes can induce apoptosis in cancer cells and control tumor progression <i>in vivo</i>. Therapeutic efficacy was particularly evident in intra-tumor setting, while depended on tumor model upon systemic administration. Thanks to their ability to deliver multiple signals, exosomes thus represent a promising therapeutic tool in cancer.

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