Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production

Clayton, Aled ORCID: https://orcid.org/0000-0002-3087-9226, Al-Taei, Saly, Webber, Jason P. ORCID: https://orcid.org/0000-0003-4772-3014, Mason, Malcolm David ORCID: https://orcid.org/0000-0003-1505-2869 and Tabi, Zsuzsanna 2011. Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. The Journal of Immunology 187 (2) , pp. 676-683. 10.4049/jimmunol.1003884

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Abstract

Extracellular adenosine is elevated in cancer tissue, and it negatively regulates local immune responses. Adenosine production from extracellular ATP has attracted attention as a mechanism of regulatory T cell-mediated immune regulation. In this study, we examined whether small vesicles secreted by cancer cells, called exosomes, contribute to extracellular adenosine production and hence modulate immune effector cells indirectly. We found exosomes from diverse cancer cell types exhibit potent ATP- and 5′AMP-phosphohydrolytic activity, partly attributed to exosomally expressed CD39 and CD73, respectively. Comparable levels of activity were seen with exosomes from pleural effusions of mesothelioma patients. In such fluids, exosomes accounted for 20% of the total ATP-hydrolytic activity. Exosomes can perform both hydrolytic steps sequentially to form adenosine from ATP. This exosome-generated adenosine can trigger a cAMP response in adenosine A2A receptor-positive but not A2A receptor-negative cells. Similarly, significantly elevated cAMP was also triggered in Jurkat cells by adding exosomes with ATP but not by adding exosomes or ATP alone. A proportion of healthy donor T cells constitutively express CD39 and/or CD73. Activation of T cells by CD3/CD28 cross-linking could be inhibited by exogenously added 5′AMP in a CD73-dependent manner. However, 5′AMP converted to adenosine by exosomes inhibits T cell activation independently of T cell CD73 expression. This T cell inhibition was mediated through the adenosine A2A receptor. In summary, the data highlight exosome enzymic activity in the production of extracellular adenosine, and this may play a contributory role in negative modulation of T cells in the tumor environment.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QR Microbiology > QR180 Immunology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Funders:	Cancer Research Wales, British Lung Foundation
Last Modified:	06 Nov 2022 14:34
URI:	https://orca.cardiff.ac.uk/id/eprint/29855

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