Melanoma cells produce adenosine through a CD38/CD73 pathway and suppress CD4+ T cell proliferation
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1
Istituto Giannina Gaslini, Italy
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2
University of Torino, Italy
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3
University of Genoa, Department of Experimental Medicine, Italy
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4
Istituto Giannina Gaslini, Italy
Nucleotide-metabolizing ectoenzymes are molecules with an extracellular catalytic domain and include i) the ADP ribosyl-cyclases CD38 and CD157, ii) ectonucleotide pyro-phosphatase/phosphodiesterase-1 (ENPP-1/PC-1), iii) ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and iv) ecto-5'-nucleotidase (CD73). These ectoenzymes regulate the extra-cellular nucleotide/nucleoside balance. Adenosine (ADO), a purine nucleoside generated by this enzymatic network, is highly concentrated in various solid tumors and promotes tumor growth by stimulating tumor angiogenesis and inhibiting anti-tumor immune responses. Moreover, inhibition of CD73 in melanoma murine models limits tumor growth and restores anti-tumor immune responses.
We investigated the expression and function of the ectoenzyme network in 3 primary and 3 continuous human melanoma cell lines. CD38 and CD73 were highly expressed in all cell lines, whereas CD39 and PC-1 expression was elevated only in 3 cell lines and low to intermediate in the others. Expression of CD157 was low in all cell lines. ADO was produced in cell lines from AMP and, to a lesser extent, from ATP and NAD+. ADO production was increased by pre-treatment of cells with a specific inhibitor of adenosine deaminase (ADA). Three primary melanoma cell lines were tested for their ability to inhibit proliferation of CD4+ T cells. All cell lines significantly inhibited proliferation, both in co-culture and in transwell systems. The inhibitory effects were reverted by pre-treating the cell lines with specific inhibitors of CD38 or CD73 (but not of PC-1 or CD39). In conclusion, we have demonstrated that melanoma (primary or established lines) cells induce immunosuppression in vivo. This effect was mediated by (ADO) produced via an ectoenzyme network, which hinges upon CD38 and CD73.
Keywords:
Melanoma,
CD38/ADP-ribosyl cyclase activity,
CD73,
Adenosine,
Immunoregulation
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune-mediated disease pathogenesis
Citation:
Morandi
F,
Horenstein
A,
Morandi
B,
Carrega
P,
Chillemi
A,
Zaccarello
G,
Mingari
MC,
Pistoia
V and
Malavasi
F
(2013). Melanoma cells produce adenosine through a CD38/CD73 pathway and suppress CD4+ T cell proliferation.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00868
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Received:
19 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Fabio Morandi, Istituto Giannina Gaslini, Genoa, Italy, fabiomorandi@gaslini.org