TY - JOUR
T1 - A non-canonical adenosinergic pathway led by CD38 in human melanoma cells induces suppression of T cell proliferation
AU - Morandi, Fabio
AU - Morandi, Barbara
AU - Horenstein, Alberto L.
AU - Chillemi, Antonella
AU - Quarona, Valeria
AU - Zaccarello, Gianluca
AU - Carrega, Paolo
AU - Ferlazzo, Guido
AU - Mingari, Maria Cristina
AU - Moretta, Lorenzo
AU - Pistoia, Vito
AU - Malavasi, Fabio
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Adenosine
KW - Ectoenzymes
KW - Immunosuppression
KW - Melanoma
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U2 - 10.18632/oncotarget.4693
DO - 10.18632/oncotarget.4693
M3 - Article
AN - SCOPUS:84944463019
VL - 6
SP - 25602
EP - 25618
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 28
ER -