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

Abstract

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 immune-modulating antitumor agents in CLL.

Selective Depletion of Regulatory T Cell Subsets by Docetaxel Treatment in Patients with Nonsmall Cell Lung Cancer

“…CD39 expressed on Tregs was reported to inhibit NK activity and promote hepatic metastatic tumor growth [36]. The increased expression of CD39 in CD4 + T cells was related to poorer prognosis [37]. We also found high expression of CD39 in aTreg cells from NCSLS patients.…”

Multidimensional scaling analysis identifies pathological and prognostically relevant profiles of circulating T‐cells in chronic lymphocytic leukemia

“…Our data show a pathological T‐cell profile already at the MBL stage, indicating that B‐cells begin to exhibit immunosuppressive function very early in the course of tumorigenesis. We found that MBL patients had an expanded compartment of highly suppressive CD39+ Treg correlating with a significantly more suppressive regulatory function, while at this stage T‐effector function only slightly deviated from healthy controls. As the T‐cell deficiencies in MBL appeared to be rather slight, antitumor responses may not be completely blunted by enhanced immunosuppression at this stage.…”

Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment

“…They suggested that CD39/adenosine pathway could contribute to “T-cell anergy” in tumors. In chronic lymphocytic leukemia, levels of circulating CD4 + CD39 + T cells significantly increased and correlated with advanced stage of the disease [32]. In a different setting than cancer, activated T cells with high CD39 expression were prone to apoptosis in older individuals and suggested that CD4 + CD39 + effector T cells do not develop into long-lived memory cells [33].…”