A non-canonical adenosinergic pathway led by CD38 in human melanoma cells induces suppression of T cell proliferation
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Fabio Morandi1,*, Barbara Morandi2,*, Alberto L. Horenstein3,*, Antonella Chillemi3, Valeria Quarona3, Gianluca Zaccarello3, Paolo Carrega4, Guido Ferlazzo5,6, Maria Cristina Mingari2, Lorenzo Moretta4, Vito Pistoia1,#, Fabio Malavasi3,#
1Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy
2Department of Experimental Medicine, University of Genoa, Genoa, Italy
3Department of Medical Sciences, Laboratory of Immunogenetics and CeRMS, University of Torino, and Transplant Immunology, Città della Salute e della Scienza, Torino, Italy
4Istituto Giannina Gaslini, Genoa, Italy
5Department of Human Pathology, University of Messina, Italy
6Cellular Therapy Program, University Hospital - A.O.U. Policlinico, Messina, Italy
*These authors have contributed equally to this work
#These authors have contributed equally to this work
Fabio Morandi, e-mail: [email protected]
Keywords: Melanoma, ectoenzymes, adenosine, immunosuppression
Received: February 27, 2015 Accepted: July 13, 2015 Published: July 25, 2015
Nucleotide-metabolizing ectoenzymes are endowed with an extracellular catalytic domain, which is involved in regulating the extracellular nucleotide/nucleoside balance. The tumor microenvironment contains high levels of adenosine (ADO) generated by this enzymatic network, thus promoting tumor growth by inhibiting anti-tumor immune responses. ADO inhibition in melanoma murine models limits tumor metastases and restores anti-tumor immune responses.
This work investigates the expression and function of ectoenzymes in primary human melanoma cell lines. All of latter cells expressed CD38, CD39, CD73, and CD203a/PC-1, and produced ADO from AMP and NAD+. Melanoma cells inhibited T cell proliferation through an ADO-dependent mechanism, since such inhibition was reverted using CD38/CD73 specific inhibitors.
Melanoma cells abolished the function of effector memory, central memory and reduced naïve CD4+ T cell proliferation. Accordingly, phosphorylation of S6 ribosomal protein, p38 and Stat1 was lower in activated memory cells than in naïve CD4+ T lymphocytes. Melanoma cells also inhibited proliferation of naïve, memory and -to a lesser extent- of effector CD8+ T cells. These different inhibitory effects correlated with distinct patterns of expression of the ADO receptor A2a and A2b. These results show that primary human melanoma cell lines suppress in vitro T cell proliferation through an adenosinergic pathway in which CD38 and CD73 play a prominent role.
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