Human Follicular Lymphoma CD39+-Infiltrating T Cells Contribute to Adenosine-Mediated T Cell Hyporesponsiveness

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 A2A/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 A2A/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 A1 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 CD25high 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 A2A/B AR as well as CD39 are novel pharmacological targets for augmenting cancer immunotherapy.

CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death

“…Considered together, the tissue distribution and enzymatic data suggest that (1) CD73 functions as a rate limiting enzyme in the activation of the adenosinergic axis and that (2) ADO production is critically restricted by CD73 expression, in turn tightly regulated by environmental signals. [41][42][43] The conclusion is that ADO production is mostly confined to the proliferation centers of the CLL LNs.…”

Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer

“…High IFN-γ serum concentrations clearly impact immunobiology and affect tumor growth. Further, pericellular adenosine the product of CD39 and CD73 interacts with T cell (A2A) adenosine receptors leading to T cell hyporesponsiveness, which is also noted in tumors [17,21]. Inhibition of CD39 by ARL 67156 can, at least in part, overcome T cell hyporesponsiveness in a subset of patients with follicular lymphoma [21].…”

Follicular lymphoma tumor–infiltrating T-helper (TH) cells have the same polyfunctional potential as normal nodal TH cells despite skewed differentiation

“…Viable SCSs were prepared as previously described. [16][17][18] All tissues were obtained under protocols approved by the University of Rochester Institutional Review Board. The pathologic and clinical data from the patients with FL are shown in Table 1.…”