Abstract
Natural killer (NK) cells are critical components of host innate immunity and function as the first line of defense against tumors and viral infection. There is increasing evidence that extracellular vesicles (EVs) are involved in the antitumor activity of NK cells. NK cell-derived EVs (NKEVs) carrying cargo such as cytotoxic proteins, microRNAs, and cytokines employ multiple mechanisms to kill tumor cells, but also exhibit immunomodulatory activity by stimulating other immune cells. Several studies have reported that NKEVs can reverse immune suppression under tolerogenic conditions and contribute to NK-mediated immune surveillance against tumors. Thus, NKEVs are a promising tool for cancer immunotherapy. In this review, we describe the biological effects and potential applications of NKEVs in antitumor immunity.
Highlights
Extracellular vesicles (EVs) are heterogeneous, membrane-bound phospholipid vesicles that are actively released by most cell types including immune and cancer cells [1]
Natural killer (NK) cells are divided into two subgroups with functional and phenotypic properties: CD56dim cells are found in the circulation and are mainly cytotoxic, whereas CD56bright cells dominate in secondary lymphoid tissues and play an immunomodulatory role by producing high levels of cytokines [3]
The soluble and/or membrane-bound forms of Fas ligand (FasL) have been detected in most NK cell-derived EVs (NKEVs) [6, 11, 15] and are thought to act via distinct mechanisms including classic receptor–ligand interaction involving the membrane receptor FasL expressed on NK92 cellderived exosomes, which exhibits time- and dose-dependent cytotoxic effects on melanoma cells [8]; and the endocytic pathway, whereby NKEVs containing soluble FasL is taken up by target cells and interacts with intracellular structures to induce FasL-mediated cell death [6]
Summary
Extracellular vesicles (EVs) are heterogeneous, membrane-bound phospholipid vesicles that are actively released by most cell types including immune and cancer cells [1]. This suggests that the functions of NK cells go beyond the traditional cell–cell interactions and paracrine signaling [6] In addition to their antitumor effects, NKEVs have immunomodulatory properties [7] and likely play a role in cancer immunotherapy. Peripheral blood mononuclear cells (PBMCs) and NK92 cells are the two major cellular sources of NKEVs. EVs derived from NK92 cells were shown to express lower levels of cytotoxic proteins than ex vivo-expanded PBMCs in several studies, but there is no evidence for the superiority of the latter cells.
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