Human follicular lymphoma CD39+-infiltrating T cells contribute to adenosine-mediated T cell hyporesponsiveness.
Our previous work has demonstrated that human follicular lymphoma (FL) infiltrating T cells are anergic, in part due to suppression by regulatory T cells. In this study, we identify pericellular adenosine, interacting with T cell-associated G protein-coupled A(2A/B) adenosine receptors (AR), as contributing to FL T cell hyporesponsiveness. In a subset of FL patient samples, treatment of lymph node mononuclear cells (LNMC) with specific A(2A/B) AR antagonists results in an increase in IFN-gamma or IL-2 secretion upon anti-CD3/CD28 Ab stimulation, as compared with that seen without inhibitors. In contrast, treatment with an A(1) AR antagonist had no effect on cytokine secretion. As the rate limiting step for adenosine generation from pericellular ATP is the ecto-ATPase CD39, we next show that inhibition of CD39 activity using the inhibitor ARL 67156 partially overcomes T cell hyporesponsiveness in a subset of patient samples. Phenotypic characterization of LNMC demonstrates populations of CD39-expressing CD4(+) and CD8(+) T cells, which are overrepresented in FL as compared with that seen in normal or reactive nodes, or normal peripheral blood. Thirty percent of the FL CD4(+)CD39(+) T cells coexpress CD25(high) and FOXP3 (consistent with regulatory T cells). Finally, FL or normal LNMC hydrolyze ATP in vitro, in a dose- and time-dependent fashion, with the rate of ATP consumption being associated with the degree of CD39(+) T cell infiltration. Together, these results support the finding that the ATP-ectonucleotidase-adenosine system mediates T cell anergy in a human tumor. In addition, these studies suggest that the A(2A/B) AR as well as CD39 are novel pharmacological targets for augmenting cancer immunotherapy.
James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
Shannon P
SP
Hilchey
James J
JJ
Kobie
Mathew R
MR
Cochran
Shelley
S
Secor-Socha
Jyh-Chiang E
JC
Wang
Ollivier
O
Hyrien
W Richard
WR
Burack
Tim R
TR
Mosmann
Sally A
SA
Quataert
Steven H
SH
Bernstein
D000241:Adenosine / Q000276:immunology / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D001081:Apyrase / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D017635:Clonal Anergy; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008224:Lymphoma, Follicular / Q000276:immunology* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; C092431:6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP; D015703:Antigens, CD; D007376:Interleukin-2; D018696:Neuroprotective Agents; D011743:Pyrimidines; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine