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Extracellular adenosine metabolism in immune cells in melanoma

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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 ectonucleotidase-positive myeloid-derived 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 co-expressed also PD-1. Ectonucleotidase expression was also up-regulated 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 anti-tumor 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 activity.

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Acknowledgments

This 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 Else-Kröner Fresenius Foundation (2010.A124, to Viktor Umansky and Alexandr V. Bazhin).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Skin Cancer Unit (G300), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Viktor Umansky, Ivan Shevchenko & Jochen Utikal

  2. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany

    Viktor Umansky, Ivan Shevchenko & Jochen Utikal

  3. Department of General Surgery, Ruprecht Karl University of Heidelberg, Heidelberg, Germany

    Ivan Shevchenko & Alexandr V. Bazhin

  4. Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich, Germany

    Alexandr V. Bazhin

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  1. Viktor Umansky
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  2. Ivan Shevchenko
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  3. Alexandr V. Bazhin
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  4. Jochen Utikal
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Correspondence to Viktor Umansky.

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This 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 report.

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Umansky, V., Shevchenko, I., Bazhin, A.V. et al. Extracellular adenosine metabolism in immune cells in melanoma. Cancer Immunol Immunother 63, 1073–1080 (2014). https://doi.org/10.1007/s00262-014-1553-8

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