Natural Killer Cell-Derived Extracellular Vesicles: Novel Players in Cancer Immunotherapy

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.

T Lymphocyte and CAR-T Cell-Derived Extracellular Vesicles and Their Applications in Cancer Therapy

“…Thus, it is conceivable that approaches directed to increase exosome secretion in CTL ex vivo can also be useful to boost exosome secretion by CAR NK cells. However, although TCR activation enhances the constitutively low secretion of exosomes by T lymphocytes, resting NK cells secrete pro-apoptotic exosomes with no differences in the amounts of exosomes or marker expression relative to activated NK cells via NK activating and inhibition receptors [ 78 , 146 ]. NK cell expansion ex vivo increases exosome secretion [ 146 ], as occurs in T lymphocytes, which constitutes an useful strategy to produce on a large scale exosomes that may lead to new preclinical and clinical applications [ 146 ].…”

“…However, although TCR activation enhances the constitutively low secretion of exosomes by T lymphocytes, resting NK cells secrete pro-apoptotic exosomes with no differences in the amounts of exosomes or marker expression relative to activated NK cells via NK activating and inhibition receptors [ 78 , 146 ]. NK cell expansion ex vivo increases exosome secretion [ 146 ], as occurs in T lymphocytes, which constitutes an useful strategy to produce on a large scale exosomes that may lead to new preclinical and clinical applications [ 146 ]. Different to T lymphocytes, NK cell recognition of their targets is not controlled by antigen specificity but rather through the integration of signals evoked by activating and inhibitory receptors, activated by a myriad of ligands in the target cells, which requires a deeper knowledge of the complex NK biology and signaling before any experimental design.…”

“…Different to T lymphocytes, NK cell recognition of their targets is not controlled by antigen specificity but rather through the integration of signals evoked by activating and inhibitory receptors, activated by a myriad of ligands in the target cells, which requires a deeper knowledge of the complex NK biology and signaling before any experimental design. This fact probably has led to CAR NK therapy being less developed than CAR T cell therapy in general [ 147 ], and therefore there are less pre-clinical trials using CAR NK-derived EV in particular [ 146 ]. However, the use of CAR NK cells has some advantages (and disadvantages) when compared with CAR T cells [ 147 ].…”

Blood Cell-Derived Microvesicles in Hematological Diseases and beyond

“…Reports on the result of this communication refer to the activation of PBMCs (both lymphocytes and monocytes) [ 144 ], to the inhibition of proliferation and/or induction of apoptosis in several tumor cell lines, and to the migratory activity and activation of ECs following stimulation of the parent cells by IL-1beta [ 145 ]. NKMVs are encountered as a promising arrow in scientists’ quiver for cancer immunotherapy due to their immunomodulatory effects and their ability to transport antitumor drugs [ 146 ].…”

Locked and Loaded: Mechanisms Regulating Natural Killer Cell Lytic Granule Biogenesis and Release

“…Engagement of these ligands with Fas (CD95) and TRAIL-R1/-R2, respectively, on the target cells can induce target cell apoptosis. Additionally, NK cells secrete biologically active extracellular vesicles (EVs) that contain cytotoxic proteins like perforin and granzymes and other immune modulatory molecules ( 14 – 17 ). These secreted vesicles seem to have immune regulatory functions and present anti-tumor effects.…”