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Updated: Dec 13, 2025
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
Targeting CD39 in cancer
Achim K Moesta1, Xian-Yang Li2, Mark J Smyth3
1Tizona Therapeutics, San Francisco, CA, USA.
Abstract:
The ATP-adenosine pathway functions as a key modulator of innate and adaptive immunity within the tumour microenvironment. Consequently, multiple clinical strategies are being explored to target this pathway for the treatment of cancer; in particular, recent clinical data with CD73 antagonists and inhibitors of A2A receptors have demonstrated the therapeutic potential of modulating this pathway. Now, inhibitors of the ectonucleotidase CD39, the rate-limiting enzyme in the conversion of ATP to immunomodulatory adenosine, are entering clinical trials. Consequently, there is currently a focus on understanding the impact of CD39 enzymatic function on innate and adaptive immunity and how therapeutic modulation of this pathway alters their functional potential within the tumour microenvironment. Recent findings reveal multipronged mechanisms of action of CD39 antagonism that rely not only on preventing the accumulation of adenosine but also on the stabilization of pro-inflammatory extracellular ATP to restore antitumour immunity. Here, we review the impact of CD39 expression and ectonucleotidase activity on immunity with a focus on the setting of oncology. Additionally, we discuss the implications for immunotherapy strategies targeting CD39, including their inclusion in rational combination therapies.
Insights
Targeting CD39 (an enzyme crucial for adenosine production) shows promise in cancer immunotherapy. Inhibiting CD39 not only reduces immunosuppressive adenosine but also stabilizes pro-inflammatory ATP, restoring anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- The ATP-adenosine pathway is a critical regulator of the tumor microenvironment's immune response.
- CD73 antagonists and A2A receptor inhibitors show therapeutic potential in cancer treatment.
- CD39 is the rate-limiting enzyme in converting ATP to adenosine, and its inhibitors are entering clinical trials.
Purpose of the Study:
- To review the impact of CD39 on innate and adaptive immunity in cancer.
- To discuss how CD39 inhibition affects the tumor microenvironment.
- To explore CD39-targeted immunotherapies and combination strategies.
Main Methods:
- Review of current literature on CD39 function in cancer immunity.
- Analysis of clinical data regarding CD73 and A2A receptor inhibitors.
- Discussion of emerging CD39 inhibitor clinical trial data.
Main Results:
- CD39 antagonism prevents adenosine accumulation and stabilizes extracellular ATP.
- CD39 inhibition restores anti-tumor immunity by modulating the tumor microenvironment.
- CD39 plays a significant role in both innate and adaptive immune responses within tumors.
Conclusions:
- CD39 antagonism offers a novel therapeutic strategy for cancer immunotherapy.
- Targeting CD39 can enhance anti-tumor immunity through multiple mechanisms.
- Combination therapies involving CD39 inhibitors hold significant promise for cancer treatment.
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