Summary and Future Perspectives
Adenosine is critically involved in a range of physiologic processes including wound healing, and its levels are tightly regulated under homeostatic conditions. In solid tumors, however, adenosine concentration is significantly elevated, predominantly due to stress-induced ATP release coupled with the overexpression of nucleotidases, such as CD39 and CD73 that contribute to its catabolism. Primarily by engaging A2AR and A2BR, also overexpressed in the TME as a result of hypoxia and inflammation, adenosine diminishes the activity of protective immune infiltrates, such as T cells, NK cells and DCs, while boosting the inhibitory capacity of immunosuppressive subsets, including Tregs and MDSCs. For instance, A2AR and A2BR-induced cAMP accumulation within T cells blunts their differentiation, proliferation, cytokine production and target cell killing, predominantly through PKA activation. Along with establishing an anti-inflammatory and tolerogenic TME, adenosine also promotes blood vessel formation and assists tumors in subverting adjacent fibroblasts to further support tumor growth and metastasis.
Administration of small molecules or mAbs with the aim to block adenosine-signaling, either by limiting its production or its binding to ARs, has yielded important tumor control in various pre-clinical tumor models. Moreover, simultaneous blockade of adenosine production and receptor binding, achieved by an anti-CD73 mAb co-administered with an A2AR antagonist, for example, have demonstrated it synergy. Given the potent suppression of T cells by adenosine, it comes as no surprise that increases in tumor control and survival conferred by ICB (anti-PD-1 and anti-CTLA-4 mAbs) or ACT, is significantly enhanced by concomitant administration of agents countering the adenosine axis. Synergy of such adenosine axis modulators has further been shown with RT, as well as CTs, schemes known to promote immunogenic cell death (i.e., ATP is released), as well as with some targeted therapies.
While blockade of adenosine production and A2AR/A2BR antagonism are being tested in the clinic as monotherapies, increasing numbers of clinical trials combining adenosine-signaling blockade with IMTs or classic treatment approaches (i.e., RT, CT and targeted therapies) are recruiting and/or underway. Given the important responses achieved by a proportion of patients to immunotherapeutic-regimens, and the tremendous levels of immunosuppression mediated by adenosine, the development of existing or new agents targeting this axis, along with further testing of combinatorial strategies, is warranted. Indeed, targeting the adenosine axis holds great promise in the improved treatment of cancer patients.