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. Author manuscript; available in PMC: 2020 Jul 1.
Published in final edited form as: Cancer Res. 2019 Oct 31;80(1):17–22. doi: 10.1158/0008-5472.CAN-19-1450

Figure 1. Overview of NK-mediated killing mechanisms.

Figure 1.

1) Antibody-dependent cell cytotoxicity (ADCC) is based on the opsonization of cancer cells by an antibody, whose Fc segment can bind to CD16 on the surface of NK cells. This creates an immunological synapse that allows NK degranulation and cytotoxicity; 2) Receptor-mediated cytotoxicity. The figure indicates 3 possible activating signals for NK-mediated degranulation and cytotoxicity: the binding of NCRs to the cancer cell surface antigen PCNA, the lack of expression of MHC-I on the surface of cancer cells, preventing the KIR-mediated inhibition of NK-killing activity, and the binding of MICA (on the surface of cancer cells) to the NK activating receptor NKG2D; 3) EV-mediated cytotoxicity. The figure indicates the secretion of EVs containing miR-186 by NK cells. These EVs can shuttle miR-186 back to NK cells where it silences receptors for TGF-β (TGFBR1 and TGFBR2) and induces downregulation of downstream signaling proteins SMAD2 and SMAD3 overall leading to resistance of NK cells to the immune-suppression mediated by TGF-β, present at high concentrations in the Tumor Microenvironment. Moreover, EVs can shuttle miR-186 to neuroblastoma (NBL) cells located also at a distance from the actual NK cell and miR-186 can directly silence MYCN and AURKA, two key oncogenes for neuroblastoma, eliciting a paracrine anti-cancer effect.