Role of Exosomes Released by Dendritic Cells and/or by Tumor Targets: Regulation of NK Cell Plasticity

Abstract

Exosomes are endosomal-derived nanovesicles released by normal and tumor cells, which transfer functionally active proteins, lipids, and nucleic acids between cells. They are important mediators of intercellular communication and act on the adjacent stroma as well as in the periphery. Recently, exosomes have been recognized to play a pathophysiological role in various diseases such as cancer or infectious diseases. Tumor cell-derived exosomes (Tex) have been shown to act as tumor promotors by educating non-malignant cells to provide a tumor supporting microenvironment, which helps to circumvent immune detection by the host and supports metastasis. However, Tex with anti-tumor, immune-activating properties were also described reflecting the complexity of exosomes. Here, we assess the role of extracellular microvesicles/exosomes as messengers affecting NK cell function in health and disease and discuss the molecular basis for the differential impact of exosomes on NK cell activity. The molecular composition/load of exosomes and the mechanisms regulating their release remain unclear and need to be further analyzed to facilitate the development of new treatment options targeting the exosomal machinery.

Keywords: NK cell regulation; dendritic cell-derived exosomes; exosomes; microvesicles; tumor derived vesicles.

Figure 1

Exosomes released from stressed or neoplastic cells can lead to NK cell activation or inhibition, which depends on a differential molecular composition. Immune-activating exosomes (e.g., Dex) often express TNF and can induce INFγ secretion and enhance cytolytic activity of NK cells. In contrast, immune suppressive exosomes often contain TGFbeta1 and NKG2D ligands and inhibit NK cell cytotoxicity. Cellular stress and mutagenesis affect the biogenesis of functional distinct exosomes. Although several features attributed to one or the other effect are described, the mechanisms leading to the respective exosome formation are still poorly understood. A major question remaining to be answered is how stress and mutagenesis affect the different sorting mechanisms responsible for the genesis of immune-activating or -suppressive vesicles. As soon as the determining pathways and their regulation are comprehensively explored, the exosome cargo will become more predictable and allow the development of new, astute strategies to employ exosomes as therapeutic tools.