Human follicular lymphoma CD39+-infiltrating T cells contribute to adenosine-mediated T cell hyporesponsiveness

SP Hilchey, JJ Kobie, MR Cochran… - The Journal of …, 2009 - journals.aai.org
SP Hilchey, JJ Kobie, MR Cochran, S Secor-Socha, JCE Wang, O Hyrien, WR Burack…
The Journal of Immunology, 2009journals.aai.org
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-γ or IL-2 secretion upon anti-CD3/CD28 Ab …
Abstract
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-γ 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.
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