Increased CD39 expression on CD4 ⁺ T lymphocytes has clinical and prognostic significance in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) cells depend on their microenvironment for proliferation and survival. Ectonucleotidase CD39 has anti-inflammatory properties as it hydrolyzes proinflammatory extracellular ATP, generates anti-inflammatory adenosine, and also protects regulatory T cells from ATP-induced cell death. In this study, we investigated the clinical significance of CD39 expression on CD4 ⁺ T cells in 62 patients with CLL as well as its compartmental regulation and explored the possible mechanisms for its induction. Compared to healthy individuals, CD4 ⁺CD39 ⁺ lymphocytes were increased in the peripheral blood of patients with CLL and correlated with the advanced stage of disease. CD4 ⁺CD39 ⁺ cells were also higher in patients with CLL, who needed therapeutic intervention, and in those who had unmutated immunoglobulin heavy chain variable region gene, were ZAP70 ⁺ or had β2-Microglobulin levels of >3 g/L. There were more CD4 ⁺CD39 ⁺ lymphocytes in the bone marrow compartment than in the peripheral blood, and in vitro studies showed that CD39 can be induced on CD4 ⁺ cells by exposure to ATP or indirectly, following B cell receptor engagement. This may support the notion that the leukemic cells contribute to create an immune-subversive environment, and perhaps to a poorer prognosis. CD39 ⁺ may also serve as a future target for the development of novel therapies with immunemodulating antitumor agents in CLL.