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Dominant immunosuppression of dendritic cell function by prostate-cancer-derived exosomes

Salimu, Josephine, Webber, Jason, Gurney, Mark, Al-Taei, Saly, Clayton, Aled and Tabi, Zsuzsanna 2017. Dominant immunosuppression of dendritic cell function by prostate-cancer-derived exosomes. Journal of Extracellular Vesicles 6 (1) , 1368823. 10.1080/20013078.2017.1368823

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Abstract

Exosomes are a distinct population of extracellular vesicles of endocytic origin with a protein repertoire similar to the parent cell. Although tumour-derived exosomes harbour immunosuppressive characteristics, they also carry tumour antigens and thus potentially contribute to immune activation. The aim of this study was to examine the impact of prostate cancer exosomes on tumour antigen cross-presentation. DU145 cells, transduced with shRNA to knockdown Rab27a (DU145KD) that inhibits exosome secretion, triggered significantly stronger tumour-antigen-specific T cell responses when loaded onto dendritic cells (DC) than control DU145 cells. Enhanced T cell response was prevented by adding purified exogenous DU145 exosomes to DU145KD cells, demonstrating that the dominant effect of tumour exosomes is immunosuppression and not antigen delivery. CD8+ T cell responses were impaired via exosomal regulation of DC function; exosomes triggered the expression of CD73, an ecto-5-nucleotidase responsible for AMP to adenosine hydrolysis, on DC. CD73 induction on DC that constitutively express CD39 resulted in an ATP-dependent inhibition of TNFα- and IL-12-production. We identified exosomal prostaglandin E2 (PGE2) as a potential driver of CD73 induction, as inhibition of PGE2 receptors significantly reduced exosome-dependent CD73 induction. The results reveal a hitherto unknown suppression of DC function via exosomal PGE2, adding a new element to tumour exosome–immune cell cross-talk.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Taylor & Francis Open
ISSN: 2001-3078
Funders: Cancer Research Wales
Date of First Compliant Deposit: 4 September 2017
Date of Acceptance: 5 August 2017
Last Modified: 27 Apr 2019 02:24
URI: http://orca.cf.ac.uk/id/eprint/104284

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