Natural Killer–Derived Exosomal miR-186 Inhibits Neuroblastoma Growth and Immune Escape Mechanisms

Abstract In neuroblastoma, the interplay between immune cells of the tumor microenvironment and cancer cells contributes to immune escape mechanisms and drug resistance. In this study, we show that natural killer (NK) cell–derived exosomes carrying the tumor suppressor microRNA (miR)-186 exhibit cytotoxicity against MYCN-amplified neuroblastoma cell lines. The cytotoxic potential of these exosomes was partly dependent upon expression of miR-186. miR-186 was downregulated in high-risk neuroblastoma patients, and its low expression represented a poor prognostic factor that directly correlated with NK activation markers (i.e., NKG2D and DNAM-1). Expression of MYCN, AURKA, TGFBR1, and TGFBR2 was directly inhibited by miR-186. Targeted delivery of miR-186 to MYCN-amplified neuroblastoma or NK cells resulted in inhibition of neuroblastoma tumorigenic potential and prevented the TGFβ1-dependent inhibition of NK cells. Altogether, these data support the investigation of a miR-186–containing nanoparticle formulation to prevent tumor growth and TGFβ1-dependent immune escape in high-risk neuroblastoma patients as well as the inclusion of ex vivo–derived NK exosomes as a potential therapeutic option alongside NK cell–based immunotherapy. Significance: These findings highlight the therapeutic potential of NK cell–derived exosomes containing the tumor suppressor miR-186 that inhibits growth, spreading, and TGFβ-dependent immune escape mechanisms in neuroblastoma.