Extracellular adenosine metabolism in immune cells

Authors: Viktor Umansky Ivan Shevchenko Alexandr V Bazhin Jochen Utikal

Publish Date: 2014/04/23

Volume: 63, Issue: 10, Pages: 1073-1080

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Abstract

Malignant melanoma is characterized by the development of chronic inflammation in the tumor microenvironment which leads to a strong immunosuppression associated with a rapid tumor progression Adenosine is considered as one of the main immunosuppressive factors in the tumor environment It is produced via enzymatic hydrolysis of extracellular ATP by ectonucleotidases CD39 and CD73 localized on cell surface Using the ret transgenic mouse melanoma model that closely mimics human melanoma we demonstrated an increased frequency of ectonucleotidasepositive myeloidderived suppressor cells MDSCs in melanoma lesions and lymphoid organs Furthermore we observed that conventional CD4+FoxP3− and CD8+ T cells infiltrating melanoma lesions of ret transgenic mice were distinctly enriched in the CD39+CD73+ subpopulation that coexpressed also PD1 Ectonucleotidase expression was also upregulated in CD4+ and CD8+ T cells upon activation In addition these ectoenzymes were largely found to be expressed on memory T cell compartment in particular on effector memory cells Our data suggest that extracellular adenosine produced by regulatory T cells Tregs and MDSCs can suppress T cell effector functions through paracrine signaling Another mechanism involves its production also by effector T cells and an inhibition of their antitumor reactivity via autocrine signaling as a part of the negative feedback loop This mode of adenosine signaling could be also used by Tregs and MDSCs to enhance their immunosuppressive activityThis paper is a Focussed Research Review based on a presentation given at the Thirteenth International Conference on Progress in Vaccination against Cancer PIVAC 13 held in Amsterdam the Netherlands October 2nd–4th 2013 It is part of a CII series of Focussed Research Reviews and meeting reportThis project has been funded by a grant from the Cooperation Program in Cancer Research between German Cancer Research Center DKFZ and Ministry of Science and Technology of Israel MOST CA157 to Viktor Umansky and by a grant from ElseKröner Fresenius Foundation 2010A124 to Viktor Umansky and Alexandr V Bazhin

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