A non-canonical adenosinergic pathway led by CD38 in human melanoma cells induces suppression of T cell proliferation.

Fabio Morandi,Lorenzo Moretta,Vito Pistoia,Fabio Malavasi,Valeria Quarona,Paolo Carrega,Alberto L Horenstein,Maria Cristina Mingari,Barbara Morandi,Gianluca Zaccarello,Antonella Chillemi,Guido Ferlazzo

doi:10.18632/oncotarget.4693

Abstract

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(+ )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.

Highlights

The adenosine (ADO) nucleoside is generated from the catabolism of several nucleotides (i.e. ATP, ADP, ADPR and AMP) or of NAD+ by nucleotide-metabolizing ectoenzymes
Melanoma cells 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
These observations indicated that melanoma cells are equipped with the complete set of molecules constituting the canonical (CD39/CD73) and alternative (CD38/CD157/ CD203a(PC-1)/CD73) pathways for ADO production

Summary

Introduction

The adenosine (ADO) nucleoside is generated from the catabolism of several nucleotides (i.e. ATP, ADP, ADPR and AMP) or of NAD+ by nucleotide-metabolizing ectoenzymes. These ectoenzymes are expressed on the outer membrane of numerous cell populations and exert their enzymatic activity in the extracellular milieu. The canonical pathway of ADO production starts from CD39, an ecto-nucleoside triphosphate diphosphohydrolase (NTPDase), which converts ATP to ADP and into AMP. The latter molecule is further converted to ADO by the 5’-nucleotidase (5’-NT) CD73 [1]. The key molecule is CD203a/PC-1, since it converts both ADPR (generated from NAD+ by CD38) or ATP to AMP, that is subsequently metabolized into ADO by CD73 [2, 3]

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Conclusion