Ectonucleoside triphosphate diphosphohydrolase-1 (E-NTPDase1/CD39) as a new prognostic marker in chronic lymphocytic leukemia

Abousamra, Nashwa K.; El-Din, Manal Salah; Elzahaf, Eman; Esmael, Mohammed E

doi:10.3109/10428194.2014.907893

Cited by 20 publications

(14 citation statements)

References 28 publications

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“…Thus, the adenosine accumulation around leukemic cells that is induced by the high CD39 expression is further enhanced by the lack of CD26, which actively suppresses the cell immunity surrounding ATLL cells, producing a favorable environment for their survival. Recently, some papers reported that in chronic lymphocytic leukemia (CLL) patients, CD39-expressing nonmalignant T lymphocytes are increased compared with in normal control, and the higher expression levels of CD39 are associated with the worse prognosis of the disease [16,36]. This information would support our results that CD39 expression on ATLL cells themselves correlates with the progression of disease through the suppression of tumor immune in the host.…”

Section: Discussionsupporting

confidence: 87%

Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function

et al. 2020

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Adult T-cell leukemia/lymphoma (ATLL) patients have an extremely poor prognosis, partly due to their immunosuppressive state. The majority of ATLL patients have leukemic cells with phenotype similar to Tregs, prompting suggestions that ATLL cells themselves have immunosuppressive functions. In this study, we detected CD39 expression on ATLL cells, particularly frequent on aggressive subtypes. CD39 and CD73 convert extracellular adenosine triphosphate (ATP) into adenosine, a key player in Tregs' immunosuppression. In vitro culture, both CD39 + ATLL cells and normal Tregs converted rapidly extracellular ATP to AMP, which was disturbed by CD39 inhibitors, and was negated in the CD39 knockout MJ cell line. The proliferation of cocultured CD4 + /CD8 + normal T cells was suppressed by CD39 + MJ cells, but not by CD39 knockout MJ cells. Supplemented ATP was exhausted by an EG7-OVA T-cell line with stable CD39 induction, but not by mock. When these cell lines were subcutaneously transplanted into murine flanks, Poly(I:C) peritoneal administration reduced tumor size to 1/3 in mock-transplanted tumors, but not in CD39 induced tumors. Overall, we found that ATLL cells express CD39 at a high rate, and our results suggest that this helps ATLL cells escape antitumor immunity through the extracellular ATPDase-Adenosine cascade. These findings will guide future clinical strategies for ATLL treatment.

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Section: Discussionsupporting

confidence: 87%

Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function

et al. 2020

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“…22 It was recently published that combinations of antibodies against CD39 and CD73 reduced the growth of different mouse tumors. 23 CD39 is found in cancers such as chronic lymphocytic leukemia 24 and subgroups of gastric cancers, 25 which makes these cancers targets for anti-CD39 antibodies and inhibitors. Although CD39 is not expressed by healthy PC, 26 we found that a large proportion of MM patients expressed CD39 on their myeloma cells.…”

Section: Open Accessmentioning

confidence: 99%

Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade

Yang

Elsaadi

Misund

et al. 2020

J Immunother Cancer

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BackgroundPD1/PDL1-directed therapies have been unsuccessful for multiple myeloma (MM), an incurable cancer of plasma cells in the bone marrow (BM). Therefore, other immune checkpoints such as extracellular adenosine and its immunosuppressive receptor should be considered. CD39 and CD73 convert extracellular ATP to adenosine, which inhibits T-cell effector functions via the adenosine receptor A2A (A2AR). We set out to investigate whether blocking the adenosine pathway could be a therapy for MM.MethodsExpression of CD39 and CD73 on BM cells from patients and T-cell proliferation were determined by flow cytometry and adenosine production by Liquid chromatograpy-mass spectrometry (HPCL/MS). ENTPD1 (CD39) mRNA expression was determined on myeloma cells from patients enrolled in the publicly available CoMMpass study. Transplantable 5T33MM myeloma cells were used to determine the effect of inhibiting CD39, CD73 and A2AR in mice in vivo.ResultsElevated level of adenosine was found in BM plasma of MM patients. Myeloma cells from patients expressed CD39, and high gene expression indicated reduced survival. CD73 was found on leukocytes and stromal cells in the BM. A CD39 inhibitor, POM-1, and an anti-CD73 antibody inhibited adenosine production and reduced T-cell suppression in vitro in coculture of myeloma and stromal cells. Blocking the adenosine pathway in vivo with a combination of Sodium polyoxotungstate (POM-1), anti-CD73, and the A2AR antagonist AZD4635 activated immune cells, increased interferon gamma production, and reduced the tumor load in a murine model of MM.ConclusionsOur data suggest that the adenosine pathway can be successfully targeted in MM and blocking this pathway could be an alternative to PD1/PDL1 inhibition for MM and other hematological cancers. Inhibitors of the adenosine pathway are available. Some are in clinical trials and they could thus reach MM patients fairly rapidly.

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“…Indeed, CD39 was reported: (i) to inversely correlate with disease stage, being expressed at higher levels in stage 0–2 CLLs compared to stages 3–4 and (ii) with therapy requirement, being higher in treatment-naïve patients. In addition, expression of CD39 is enriched in samples carrying mutated IGHV genes, a common feature in good prognosis CLL subset [ 53 , 54 ]. Accordingly, CD39 ATPase and ADPase activities are enhanced in stage 0–2 CLL than in stage 3–4 [ 55 ].…”

Section: Expression Of the Adenosinergic Axis Machinery On Cll Celmentioning

confidence: 99%

“…Consistently, CD39 + T lymphocytes are enriched in CLL patients that need to be treated, compared to untreated patients [ 56 , 57 ]. Ultimately, T-cell CD39 expression is considered predictive of treatment requirement, as a significantly shorter time to first treatment (TTFT) was observed in patients with CD39 high T cells compared to CD39 low [ 54 ].…”

Section: Expression Of the Adenosinergic Axis Machinery On Cll Celmentioning

confidence: 99%

Targeting the Adenosinergic Axis in Chronic Lymphocytic Leukemia: A Way to Disrupt the Tumor Niche?

Vaisitti

Arruga

Deaglio

2018

IJMS

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Targeting adenosine triphosphate (ATP) metabolism and adenosinergic signaling in cancer is gaining momentum, as increasing evidence is showing their relevance in tumor immunology and biology. Chronic lymphocytic leukemia (CLL) results from the expansion of a population of mature B cells that progressively occupies the bone marrow (BM), the blood, and peripheral lymphoid organs. Notwithstanding significant progress in the treatment of these patients, the cure remains an unmet clinical need, suggesting that novel drugs or drug combinations are needed. A unique feature of CLL is its reliance on micro-environmental signals for proliferation and cell survival. We and others have shown that the lymphoid niche, an area of intense interactions between leukemic and bystander non-tumor cells, is a typically hypoxic environment. Here adenosine is generated by leukemic cells, as well as by cells of myeloid origin, acting through autocrine and paracrine mechanisms, ultimately affecting tumor growth, limiting drug responses, and skewing the immune cells towards a tolerant phenotype. Hence, understanding the mechanisms through which this complex network of enzymes, receptors, and metabolites functions in CLL, will pave the way to the use of pharmacological agents targeting the system, which, in combination with drugs targeting leukemic cells, may get us one step closer to curing these patients.

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Ectonucleoside triphosphate diphosphohydrolase-1 (E-NTPDase1/CD39) as a new prognostic marker in chronic lymphocytic leukemia

Cited by 20 publications

References 28 publications

Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function

Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function

Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade

Targeting the Adenosinergic Axis in Chronic Lymphocytic Leukemia: A Way to Disrupt the Tumor Niche?

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