Targeting CD39 in cancer

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.

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Fig. 1: The ATP–ADO axis in the TME.
Fig. 2: Therapeutic inhibition of CD39 ectonucleotidase activity enhances antitumour immunity by multiple mechanisms in the TME.
Fig. 3: Targeting CD39 in combination with other cancer therapies.
Fig. 4: The yin and yang of ATP and ADO in the TME.

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Acknowledgements

The authors thank members of their laboratories and H. Deng (The Fourth Affiliated Hospital of Nanchang University) for figure preparation. M.J.S. was supported by a National Health and Medical Research Council (NH&MRC) Investigator Fellowship (1173958) and Program Grant (1132519) and a Melanoma Research Alliance Established Investigator Award (611295).

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A.K.M. and M.J.S. wrote the initial draft and X.-Y.L. prepared the figures and helped with manuscript referencing and editing.

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Correspondence to Mark J. Smyth.

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M.J.S. has research agreements with Bristol Myers Squibb and Tizona Therapeutics, and is on the Scientific Advisory Board of Tizona Therapeutics and Compass Therapeutics. A.K.M. is an employee of Tizona Therapeutics.

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Nature Reviews Immunology thanks F. Quintana, M. Sitkovsky and J. Wischhuse for their contribution to the peer review of this work.

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Moesta, A.K., Li, X. & Smyth, M.J. Targeting CD39 in cancer. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-0376-4

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