Targeting adenosine for cancer immunotherapy

Abstract

Immune checkpoint antagonists (CTLA-4 and PD-1/PD-L1) and CAR T-cell therapies generate unparalleled durable responses in several cancers and have firmly established immunotherapy as a new pillar of cancer therapy. To extend the impact of immunotherapy to more patients and a broader range of cancers, targeting additional mechanisms of tumor immune evasion will be critical. Adenosine signaling has emerged as a key metabolic pathway that regulates tumor immunity. Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment. Hypoxia, high cell turnover, and expression of CD39 and CD73 are important factors in adenosine production. Adenosine signaling through the A2a receptor expressed on immune cells potently dampens immune responses in inflamed tissues. In this article, we will describe the role of adenosine signaling in regulating tumor immunity, highlighting potential therapeutic targets in the pathway. We will also review preclinical data for each target and provide an update of current clinical activity within the field. Together, current data suggest that rational combination immunotherapy strategies that incorporate inhibitors of the hypoxia-CD39-CD73-A2aR pathway have great promise for further improving clinical outcomes in cancer patients.

Keywords: A2a receptor; Adenosine; CD39; CD73; CTLA-4; Checkpoint blockade; Immunotherapy; PD-1.

Fig. 1

Extracellular Adenosine Creates a Highly Immunosuppressive Microenvironment. ATP in tumor tissue is released from cellular breakdown as well as vesicular and/or channel-mediated release. Adenosine is generated from enzymatic dephosphorylation of ATP, as well as direct release from tumor cells. While ATP functions as a danger signal for immune response, adenosine is an immunosuppressive metabolite, signaling largely through the A2aR and A2b receptors on a wide range of innate and adaptive immune cells. Inhibiting agents presently in clinical trials are depicted in red; agents targeting hypoxia and CD39 are in preclinical stage of development and are depicted in blue. Agents targeting the A2b receptor are in various stages of development, but are not depicted