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

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

Research output: Contribution to journalArticle

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+. 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.

Original languageEnglish
Pages (from-to)25602-25618
Number of pages17
JournalOncotarget
Volume6
Issue number28
DOIs
Publication statusPublished - 2015

Keywords

  • Adenosine
  • Ectoenzymes
  • Immunosuppression
  • Melanoma

ASJC Scopus subject areas

  • Oncology

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    Morandi, F., Morandi, B., Horenstein, A. L., Chillemi, A., Quarona, V., Zaccarello, G., Carrega, P., Ferlazzo, G., Mingari, M. C., Moretta, L., Pistoia, V., & Malavasi, F. (2015). A non-canonical adenosinergic pathway led by CD38 in human melanoma cells induces suppression of T cell proliferation. Oncotarget, 6(28), 25602-25618. https://doi.org/10.18632/oncotarget.4693