Cancer immunotherapy based on immune-checkpoint inhibition or adoptive cell therapy has revolutionized cancer care. Nevertheless, a large proportion of patients do not benefit from such treatments. Over the past decade, remarkable progress has been made in the development of ‘next-generation’ therapeutics in immuno-oncology, with inhibitors of extracellular adenosine (eADO) signalling constituting an expanding class of agents. Induced by tissue hypoxia, inflammation, tissue repair and specific oncogenic pathways, the adenosinergic axis is a broadly immunosuppressive pathway that regulates both innate and adaptive immune responses. Inhibition of eADO-generating enzymes and/or eADO receptors can promote antitumour immunity through multiple mechanisms, including enhancement of T cell and natural killer cell function, suppression of the pro-tumourigenic effects of myeloid cells and other immunoregulatory cells, and promotion of antigen presentation. With several clinical trials currently evaluating inhibitors of the eADO pathway in patients with cancer, we herein review the pathophysiological function of eADO with a focus on effects on antitumour immunity. We also discuss the treatment opportunities, potential limitations and biomarker-based strategies related to adenosine-targeted therapy in oncology.
Abundant evidence indicates that the conversion of pro-inflammatory extracellular ATP into immunosuppressive extracellular adenosine (eADO) favours tumour progression and escape from antitumour immunity.
The production of eADO primarily involves the concerted action of the cell-surface ectonucleotidases CD39 and CD73; however, alternative pathways involve the enzymatic activity of tissue-non-specific alkaline phosphatases and the NAD+ ectohydrolase CD38 as well as cellular export of cytosolic adenosine.
Activation of adenosine receptors A2A and A2B on tumour-infiltrating immune cells suppresses the antitumour activities of these cells; A2B signalling in tumour cells themselves further promotes their survival and metastasis.
In preclinical models, targeted inhibition of CD73, CD39, CD38, A2A or A2B can restore antitumour immunity and enhance the efficacy of cancer immunotherapies.
Clinical trials investigating the antitumour activity of eADO pathway inhibitors in patients with cancer are underway and preliminary evidence of therapeutic efficacy has been reported.
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The work of D.A. is supported by a doctoral scholarship from the Fonds Recherche Santé – Québec. The work of J.S. is supported by research grants from the Canadian Institutes of Health Research, the Terry Fox Research Institute and the Canadian Cancer Society. J.S. acknowledges research support from the Jean-Guy Sabourin Research Chair in Pharmacology.
J.S. is a permanent member of the scientific advisory board and holds stocks of Surface Oncology. The other authors declare no competing interests.
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Nature Reviews Clinical Oncology thanks the four anonymous reviewers for their contribution to the peer review of this work.
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Allard, B., Allard, D., Buisseret, L. et al. The adenosine pathway in immuno-oncology. Nat Rev Clin Oncol 17, 611–629 (2020). https://doi.org/10.1038/s41571-020-0382-2
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