Increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer.
OBJECTIVE
Regulatory T cell (Treg) frequency and activity are increased in cancer patients and play a major role in tumor escape. Although disease progression is favored by the presence of Treg, mechanisms used by Treg to suppress antitumor immunity are unknown. The ectonucleotidases CD39 and CD73 are expressed in Treg and convert ATP into immunosuppressive adenosine. In this study, the involvement of the adenosinergic pathway in Treg-mediated suppression in head and neck squamous cell carcinoma (HNSCC) patients was evaluated.


METHODS
HNSCC patients with an active disease (n = 19) and patients with no evident disease after therapy (n = 14) were studied. Ectonucleotidase expression on CD4(+) T cells and CD4(+)CD25(high) Treg was evaluated by flow cytometry and compared with normal controls. Ectonucleotidase activity was also compared within these three groups. The data were analyzed for associations of ectonucleotidase expression/function with disease stage.


RESULTS
The percentages and expression levels of CD39 and CD73 in CD4(+) T cells and Treg were greater in HNSCC than in normal controls and highest in patients with no evident disease. Patients' Treg hydrolyzed ATP at higher rates and produced higher levels of adenosine than normal controls' Treg. The increased frequency and enzymatic activity of CD4(+)CD39(+) cells corresponded to increased adenosine-mediated suppression of effector T cells, which was partly inhibited by ARL67156, an ectonucleotidase inhibitor, and by ZM241385, a selective A(2a)/A(2b) receptor antagonist.


CONCLUSIONS
CD39(+) Treg frequency and adenosine-mediated suppression are significantly increased in HNSCC patients. The adenosinergic pathway is involved in Treg-mediated immunosuppression in cancer and its attenuation could be a promising immunotherapeutic strategy for patients with HNSCC.
Mandapathil
Magis
M
University of Pittsburgh Cancer Institute and Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Szczepanski
Miroslaw J
MJ
Szajnik
Marta
M
Ren
Jin
J
Lenzner
Diana E
DE
Jackson
Edwin K
EK
Gorelik
Elieser
E
Lang
Stephan
S
Johnson
Jonas T
JT
Whiteside
Theresa L
TL
D015720:5'-Nucleotidase / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
D015703:Antigens, CD; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase; D009699:N-Glycosyl Hydrolases; C019599:adenosine nucleosidase; D001081:Apyrase; C067869:CD39 antigen