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Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

Higuchi H 1 , Yamakawa N 1 , Imadome KI 2 , Yahata T 3 , Kotaki R 1 , Ogata J 1 Show all authors , Kakizaki M 4 , Fujita K 5 , Lu J 6 , Yokoyama K 1 , Okuyama K 1 , Sato A 7 , Takamatsu M 1 , Kurosaki N 1 , Alba SM 1 , Azhim A 8 , Horie R 9 , Watanabe T 10 , Kitamura T 11 , Ando K 7 , Kashiwagi T 12 , Matsui T 12 , Okamoto A 13 , Handa H 14 , Kuroda M 5 , Nakamura N 15 , Kotani A 1

Affiliations 

  • 1 Department of Hematological Malignancy, Institute of Medical Science, Tokai University, Isehara, Kanagawa, Japan
  • 2 Department of Infectious Diseases, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan
  • 3 Research Center for Cancer Stem Cell and
  • 4 Department of Gastroenterology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
  • 5 Department of Molecular Pathology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan
  • 6 Department of Intractable Diseases, Institute of National Center for Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan
  • 7 Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
  • 8 Department of Biotechnology, Kulliyyah of Science, International Islamic University Malaysia, Kuantan, Malaysia
  • 9 Department of Hematology, School of Medicine, Kitasato University, Sagamihara, Kanagawa, Japan
  • 10 Department of Medical Genome Sciences, Graduate School of Frontier Sciences, and
  • 11 Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
  • 12 Department of Internal Medicine, Nishiwaki Municipal Hospital, Nishiwaki, Hyogo, Japan
  • 13 Department of Hematology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
  • 14 Department of Medicine and Clinical Science, Gunma University, Maebashi, Gunma, Japan
  • 15 Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
Blood, 2018 06 07;131(23):2552-2567.
PMID: 29685921 DOI: 10.1182/blood-2017-07-794529

Abstract

Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin's lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBV-encoded RNA. We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-α, and arginase 1, suggesting the immune regulatory role of BART miRNAs. The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma. These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV+ B-cell lymphoma.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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