Abstract
Tumor-derived extracellular vesicles (EVs), as tumor vaccines, carry tumor-associated antigens (TAAs), and were expected to transfer TAAs to antigen-presenting cells. However, treatment with tumor-derived EVs exhibited no obvious antitumor effect on the established tumors, likely due to their immuno-suppressive functions, and also to the poor immunogenicity of TAAs. In order to improve the immune stimulating properties, EVs expressing a highly immunogenic bacterial antigen, 6 kDa early secretory antigenic target (ESAT-6), from Mycobacterium tuberculosis were prepared by genetically modifying the parent tumor cells with a plasmid coding for ESAT-6. Cultured B16 tumor cells were transfected with a ternary complex system consisting of pDNA, polyethylenimine (PEI), and chondroitin sulfate. The cells that were transfected with the ternary complex secreted EVs with a higher number of ESAT-6 epitopes than those transfected by a conventional DNA/PEI binary complex, due to the low cytotoxicity, and durable high expression efficiency of the ternary complex systems. The EVs presenting the ESAT-6 epitope (ESAT-EV) were collected and explored as immune modulatory agents. Dendritic cells (DCs) were differentiated from mouse bone marrow cells and incubated with ESAT-EV. After incubating with the EVs for one day, the DCs expressed a significantly higher level of DC maturation marker, CD86. The DCs treated with ESAT-EV showed a significantly improved antitumor activity in tumor-bearing mice.
Highlights
Extracellular vesicles (EVs) including exosomes that are derived from tumor cells are known to carry an array of tumor-associated antigens (TAAs)
Transfection was carried out by a ternary complex system consisting of DNA, Polyethylenimine (PEI), and chondroitin sulfate (CS), or by a conventional binary complex without CS
Transfection with the DNA/PEI/CS ternary complex only slightly affected the yield of extracellular vesicles (EVs), and almost the same amount of ESAT-EV was obtained as Naive EV
Summary
Extracellular vesicles (EVs) including exosomes that are derived from tumor cells are known to carry an array of tumor-associated antigens (TAAs). They were expected to be ideal candidates for use in tumor vaccines to transfer the TAAs to antigen-presenting cells (APCs) [1]. The polyepitopic antigen presentation on tumor-derived EVs could potentially elicit appropriate immune responses against tumors [2]. The administration of exosomes from brain tumor cell lines into syngeneic animals has resulted in the rejection of subsequent challenges of the same tumor, inducing both humoral and cellular immune responses [4]. Despite hoping that tumor-derived EVs would be promising
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