A non-canonical adenosinergic pathway led by CD38 in human melanoma cells induces suppression of T cell proliferation.
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.
Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy.
Fabio
F
Morandi
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Barbara
B
Morandi
Department of Medical Sciences, Laboratory of Immunogenetics and CeRMS, University of Torino, and Transplant Immunology, Città della Salute e della Scienza, Torino, Italy.
Alberto L
AL
Horenstein
Department of Medical Sciences, Laboratory of Immunogenetics and CeRMS, University of Torino, and Transplant Immunology, Città della Salute e della Scienza, Torino, Italy.
Antonella
A
Chillemi
Department of Medical Sciences, Laboratory of Immunogenetics and CeRMS, University of Torino, and Transplant Immunology, Città della Salute e della Scienza, Torino, Italy.
Valeria
V
Quarona
Department of Medical Sciences, Laboratory of Immunogenetics and CeRMS, University of Torino, and Transplant Immunology, Città della Salute e della Scienza, Torino, Italy.
Gianluca
G
Zaccarello
Istituto Giannina Gaslini, Genoa, Italy.
Paolo
P
Carrega
Department of Human Pathology, University of Messina, Italy.|Cellular Therapy Program, University Hospital - A.O.U. Policlinico, Messina, Italy.
Guido
G
Ferlazzo
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Maria Cristina
MC
Mingari
Istituto Giannina Gaslini, Genoa, Italy.
Lorenzo
L
Moretta
Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy.
Vito
V
Pistoia
Department of Medical Sciences, Laboratory of Immunogenetics and CeRMS, University of Torino, and Transplant Immunology, Città della Salute e della Scienza, Torino, Italy.
Fabio
F
Malavasi
D015720:5'-Nucleotidase / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology / Q000378:metabolism*; D000241:Adenosine / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D007700:Kinetics; D008213:Lymphocyte Activation; D008545:Melanoma / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology
D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D015720:5'-Nucleotidase; C548241:NT5E protein, human; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D000241:Adenosine
adenosine; ectoenzymes; immunosuppression; melanoma