The function and clinical application of extracellular vesicles in innate immune regulation

Abstract

The innate immune system plays a crucial role in the host defense against viral and microbial infection. Exosomes constitute a subset of extracellular vesicles (EVs) that can be released by almost all cell types. Owing to their capacity to shield the payload from degradation and to evade recognition and subsequent removal by the immune system, exosomes efficiently transport functional components to recipient cells. Accumulating evidence has recently shown that exosomes derived from tumor cells, host cells and even bacteria and parasites mediate the communication between the invader and innate immune cells and thus play an irreplaceable function in the dissemination of pathogens and donor cell-derived molecules, modulating the innate immune responses of the host. In this review, we describe the current understanding of EVs (mainly focusing on exosomes) and summarize and discuss their crucial roles in determining innate immune responses. Additionally, we discuss the potential of using exosomes as biomarkers and cancer vaccines in diagnostic and therapeutic applications.

Keywords: cancer diagnosis; exosome; extracellular vesicles; immunotherapy; innate immune.

Fig. 1

Exosome biogenesis and composition. Exosomes originate not only from ILVs in MVBs but also from plasma membrane budding. Early endosomes maturate into late endosomes/MVBs, which follow either the secretory or the degradative pathway. Microvesicles are generated by budding from the cytomembrane. Apoptotic bodies are generated during programmed cell death (left). Exosomes have spherical structures consisting of a lipid bilayer and contain complex contents, including proteins, mRNA, miRNA, ncRNA, and DNA (right)

Fig. 2

Functions of exosomes in innate immunity. a Activated T cell-derived exosomes containing DNA are transferred to DCs, inducing an antiviral IFN response; RNA-bearing exosomes secreted by virus-infected cells activate the innate immune system of DCs; and irradiated cancer cells deliver tumor dsDNA to DCs via exosomes, leading to DC activation and IFN I release. b Tumor cells secrete and transfer EGFR⁺ exosomes to macrophages, which interfere with innate antiviral immunity via MEKK2-mediated deregulation of IRF3, and tumor-derived microvesicles/exosomes containing a ligand for NKG2D downregulate NKG2D expression on DCs and inhibit the cytotoxic activity of DCs. c ODN-loaded extracellular vesicles derived from TLR9-activated macrophages are transported to naïve macrophages and induce the release of chemokine TNF-α; tumor-secreted miR-21 and miR-29a bind with TLR7 and TLR8 in macrophages, triggering a prometastatic inflammatory response; and TEXs containing HSP70/HSP72 activate NF-κB signaling through TLR2 on MDSCs or MSCs

Fig. 3

Exosomes in cancer diagnostic and therapeutic applications. a Exosomes bearing certain proteins, miRNAs or DNA may be valuable as cancer biomarkers in liquid biopsy samples. The test results may provide meaningful guidance for disease screening, prognosis, diagnosis, risk assessment, clinical decisions, and personalized treatment. b Exosomes derived from M1-polarized macrophages or NK cells may be used as vaccine adjuvants, and radiation-induced tumor DNA-loaded exosomes or antigen-loaded DC exosomes are potential vaccines for cancer treatment