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Research Article

Natural Killer-derived exosomal miR-186 inhibits neuroblastoma growth and immune escape mechanisms.

Paolo Neviani, Petra M Wise, Mariam Murtadha, Cathy W Liu, Chun-hua Wu, Ambrose Y Jong, Robert C Seeger and Muller Fabbri
Paolo Neviani
Pediatrics- Hematology Oncology, and Microbiology Immunology Keck School of Medicine, Childrens' Hospital Los Angeles- University of Southern California
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Petra M Wise
Division of Cancer Research, Charles R. Drew University of Medicine and Science
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Mariam Murtadha
Pediatrics- Hematology Oncology, and Microbiology Immunology Keck School of Medicine, Childrens' Hospital Los Angeles- University of Southern California
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Cathy W Liu
Division of Hematology - Oncology and Saban Research Institute, Children's Hospital of Los Angeles
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Chun-hua Wu
pediatrics, Children's Hospital of Los Angeles
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Ambrose Y Jong
pediatrics, Children's Hospital of Los Angeles
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Robert C Seeger
Department of Pediatrics, Keck School of Medicine, University of Southern California, Children's Hospital Los Angeles and the Saban Research Institute
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Muller Fabbri
University of Hawaii Cancer Center, University of Hawaii at Manoa
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  • ORCID record for Muller Fabbri
  • For correspondence: mfabbri@cc.hawaii.edu
DOI: 10.1158/0008-5472.CAN-18-0779
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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 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, TGFΒR1 and TGFΒR2 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 TGFb1-dependent inhibition of NK cells. Altogether, these data support the investigation of a miR-186-containing nanoparticle formulation to prevent tumor growth and TGFb1-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.

  • Received March 12, 2018.
  • Revision received October 24, 2018.
  • Accepted December 6, 2018.
  • Copyright ©2018, American Association for Cancer Research.

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Published OnlineFirst December 12, 2018
doi: 10.1158/0008-5472.CAN-18-0779

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Natural Killer-derived exosomal miR-186 inhibits neuroblastoma growth and immune escape mechanisms.
Paolo Neviani, Petra M Wise, Mariam Murtadha, Cathy W Liu, Chun-hua Wu, Ambrose Y Jong, Robert C Seeger and Muller Fabbri
Cancer Res December 12 2018 DOI: 10.1158/0008-5472.CAN-18-0779

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Natural Killer-derived exosomal miR-186 inhibits neuroblastoma growth and immune escape mechanisms.
Paolo Neviani, Petra M Wise, Mariam Murtadha, Cathy W Liu, Chun-hua Wu, Ambrose Y Jong, Robert C Seeger and Muller Fabbri
Cancer Res December 12 2018 DOI: 10.1158/0008-5472.CAN-18-0779
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Cancer Research Online ISSN: 1538-7445
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