Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

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, A_2AR, A_2BR, 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.

Keywords: Adenosine; Adenosine receptors; cancer immunotherapy; immune cells; tumor cells.

Figure 1

Generation of adenosine in the tumor microenvironment leads to the suppression of multiple immune subsets. Arrows indicate increased expression or activation. T bars indicate inhibition or reduced activity.

Figure 2

Expression of adenosine receptors and their downstream signalling pathways within various immune cell subsets and tumor cells in the context of the TME. Arrows indicate increased expression or activation. T bars indicate inhibition or reduced activity.