LAUSR

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. Signalling induced by extracellular adenosine (eADO) can suppress antitumour immunity through multiple mechanisms. Herein, the authors review the pathophysiological functions of eADO in cancer and the related prognostic implications. They discuss the associated opportunities for eADO pathway-targeted immunotherapy, highlighting potential limitations and the scope for combination and biomarker-based strategies. The data emerging from oncology clinical trials of the diverse range of therapies that have been developed to target the eADO signalling pathway are also described. 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 A2 A and A2 B on tumour-infiltrating immune cells suppresses the antitumour activities of these cells; A2 B signalling in tumour cells themselves further promotes their survival and metastasis. In preclinical models, targeted inhibition of CD73, CD39, CD38, A2 A or A2 B 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.