Abstract
The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of ‘checkpoint blockade’ and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient’s own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function. The production of extracellular adenosine is mediated by the cell surface ectoenzymes CD73, CD39, and CD38 and therapeutic agents have been developed to target these as well as the downstream adenosine receptors (A1R, A2AR, A2BR, A3R) to enhance anti-tumor immune responses. This review will discuss the role of adenosine and adenosine receptor signaling in tumor and immune cells with a focus on their cell-specific function and their potential as targets in cancer immunotherapy.
Highlights
Adenosine triphosphate (ATP) is a ubiquitous molecule that plays a vital role as the universal energy currency within the cell
Reflecting the important role of ADO in the tumor context, CD39, CD73, and CD38 ectoenzymes have been identified as potential biomarkers for clinical outcomes in chemo- and immune-therapies and to identify immune subsets that may be responsible for immunosuppression or are in an exhausted state
Mice deficient for members of this pathway, including CD73, CD39, and A2AR, exhibit mild autoimmune phenotypes compared to mice lacking other immune checkpoints such as PD-1 and CTLA-4, the potential remains for unwanted autoimmune/inflammatory side-effects
Summary
Adenosine triphosphate (ATP) is a ubiquitous molecule that plays a vital role as the universal energy currency within the cell. Under certain conditions, such as tissue injury, inflammation, ischemia, or in the tumor microenvironment (TME), extracellular ATP levels increase due to release from inflammatory, apoptotic, or necrotic cells [3]. Due to the presence of high concentrations of ADO within the TME and the expression of ADO receptors on tumor and immune cells, the role of ADO in cancer progression and anti-tumor immune responses have been intensively investigated. This has led to the clinical development of antibodies and small molecule inhibitors targeting various components of the ADO pathway including CD39, CD38, CD73, A2AR, and A2BR. This review will discuss the signaling pathways in which ADO receptors mediate their effect in both tumor and immune cells, and recent progress in targeting the ADO pathway to improve immunotherapies
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