Dendritic cell-derived exosomes in cancer immunotherapy: exploiting nature's antigen delivery pathway

Dendritic cells release large quantities of exosomes, known as dexosomes. These dexosomes are heat-stable, small vesicles (60-90 nm in diameter) made up of a lipid bilayer displaying an enrichment in sphingomyelin and a decrease in phosphatidylcholine content with no measurable asymmetry. They incorporate a characteristic set of proteins, including a large quantity of tetraspanins such as CD9 and CD81, all the known antigen presenting molecules (major histocompatibility complex class I and II, CD1 a, b, c and d) and the costimulatory molecule CD86. The function of dexosomes is to transfer antigen-loaded major histocompatibility complex class I and II molecules, and other associated molecules, to naive dendritic cells, potentially leading to the amplification of the cellular immune response. In preclinical mouse models, antigen-loaded dexosomes elicit strong antitumor activity. Human dexosomes can be prepared ex vivo relatively easily from dendritic cells derived from monocytes isolated by leukapheresis of healthy individuals or cancer patients. The feasibility of using dexosomes as a cancer therapeutic vaccine has been tested in two Phase I clinical studies in melanoma and lung cancer patients, respectively. These studies demonstrate that dexosomes can be prepared from cancer patient blood cells and be safely administered. Clinical observations suggested that dexosomes can stimulate both the adaptive (T-cells) and innate (natural killer cells) cellular immune responses. This review focuses on the perspective of using dexosomes in cancer immunotherapy. Concepts for using the exosome pathway in other possible pharmacologic applications are also discussed.