Abstract
Immune therapeutic exosomes, derived exogenously from dendritic cells (DCs), the ‘directors’ of the immune response, are receiving favorable safety and tolerance profiles in phase I and II clinical trials for a growing number of inflammatory and neoplastic diseases. DC-derived exosomes (EXO), the focus of this review, can be custom tailored with immunoregulatory or immunostimulatory molecules for specific immune cell targeting. Moreover, the relative stability, small size and rapid uptake of EXO by recipient immune cells offer intriguing options for therapeutic purposes. This necessitates an in-depth understanding of mechanisms of EXO biogenesis, uptake and routing by recipient immune cells, as well as their in vivo biodistribution. Against this backdrop is recognition of endogenous exosomes, secreted by all cells, the molecular content of which is reflective of the metabolic state of these cells. In this regard, exosome biogenesis and secretion is regulated by cell stressors of chronic inflammation and tumorigenesis, including dysbiotic microbes, reactive oxygen species and DNA damage. Such cell stressors can promote premature senescence in young cells through the senescence associated secretory phenotype (SASP). Pathological exosomes of the SASP amplify inflammatory signaling in stressed cells in an autocrine fashion or promote inflammatory signaling to normal neighboring cells in paracrine, without the requirement of cell-to-cell contact. In summary, we review relevant lessons learned from the use of exogenous DC exosomes for immune therapy, as well as the pathogenic potential of endogenous DC exosomes.
Highlights
The overall goal of immune therapy is to restore homeostasis or health
The goal of this review is to summarize lessons learned from the use of exogenous dendritic cells (DCs) EXO as immune therapy for chronic diseases, juxtaposed upon the pathogenic potential of endogenously induced DC EXO in infectious/inflammatory diseases
Formation of multivesicular bodies (MVBs) and EXO is driven by the endosomal sorting complex required for transport (ESCRT), which is composed of four protein complexes (ESCRT-0, -I, -II and -III) with associated proteins (VPS4, VTA1, ALIX)
Summary
The overall goal of immune therapy is to restore homeostasis or health. Depending on the threat received, immune therapy can consist of various adjuvants or immune checkpoint inhibitors to stimulate tumor destruction or eliminate intracellular pathogens. The unique capability of DCs to direct these responses has fueled immense interest in their use in immune therapy, for example, by using genetically modified DCs or DCs armed with immunosuppressive cytokines to suppress inflammatory disease in animals The limitations of such therapy include the rarity of DCs and Treg in vivo and phenotypic instability of DCs [13]. EXO can retain sensitive cargo, including proteins, miRNA, mRNA, DNA and lipids, and transfer that cargo to distant sites in the body, where functions of target cells can be modified. EXO released from cells are endowed with surface adhesion molecules and other proteins that promote intercellular communication and uptake by recipient cells. Enzymes such as elongation factors and glyceraldehyde 3-phosphate dehydrogenase are expressed in EXO
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