Unlocking antitumor immunity with adenosine receptor blockers

Victoria A Remley; Joel Linden; Todd W Bauer; Julien Dimastromatteo

doi:10.20517/cdr.2023.63

Unlocking antitumor immunity with adenosine receptor blockers

Cancer Drug Resist. 2023 Oct 25;6(4):748-767. doi: 10.20517/cdr.2023.63. eCollection 2023.

Authors

Victoria A Remley^{1

2}, Joel Linden³, Todd W Bauer^{1

2}, Julien Dimastromatteo³

Affiliations

¹ Department of Surgery, University of Virginia, Charlottesville, VA 22903, USA.
² University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22903, USA.
³ Adovate, Charlottesville, VA 22901, USA.

Abstract

Tumors survive by creating a tumor microenvironment (TME) that suppresses antitumor immunity. The TME suppresses the immune system by limiting antigen presentation, inhibiting lymphocyte and natural killer (NK) cell activation, and facilitating T cell exhaustion. Checkpoint inhibitors like anti-PD-1 and anti-CTLA4 are immunostimulatory antibodies, and their blockade extends the survival of some but not all cancer patients. Extracellular adenosine triphosphate (ATP) is abundant in inflamed tumors, and its metabolite, adenosine (ADO), is a driver of immunosuppression mediated by adenosine A2A receptors (A2AR) and adenosine A2B receptors (A2BR) found on tumor-associated lymphoid and myeloid cells. This review will focus on adenosine as a key checkpoint inhibitor-like immunosuppressive player in the TME and how reducing adenosine production or blocking A2AR and A2BR enhances antitumor immunity.

Keywords: Immunotherapy; adenosine; adenosine A2A receptors (A2AR); adenosine A2B receptors (A2BR); adenosine receptors; immune cells; tumor cells; tumor microenvironment.

Publication types

Review