Unlocking antitumor immunity with adenosine receptor blockers

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.

Figure 1

Adenosine’s pleiotropic effects on immune cells. ADO facilitates the evasion of tumor cells from immune detection by restricting the activity of T cells, DCs, NK cells, macrophages, and neutrophils. Concurrently, adenosine amplifies the functionality of immunosuppressive cell types like MDSCs and Tregs. ADO: Adenosine; A2AR: A2A receptors; A2BR: A2B receptors; DCs: dendritic cells; MDSCs: myeloid-derived suppressor cells; NK: natural killer; TNFα: tumor necrosis factor-alpha; Tregs: regulatory T cells; VEGF: vascular endothelial growth factor.

Figure 2

Adenosine Biosynthesis in Inflamed Tissues. The accumulation of extracellular ATP, driven by stress-induced conditions, stimulates extracellular ADO production by the enzymes CD39 and CD73. ADO binds four G protein-coupled receptors, A1, A2A, A2B, and A3. ADO: Adenosine; ADP: adenosine diphosphate; AMP: adenosine monophosphate; ATP: adenosine triphosphate.

Figure 3

Hypoxia in the TME. This figure illustrates a region of a tumor devoid of vasculature, leading to an oxygen-starved environment. This hypoxic zone is characterized by low pH and a predominance of lactate. Within this environment, TAMs tend to adopt an M2 phenotype, and Tregs become the predominant T cell population. Hypoxic conditions also encourage the expression of the ectoenzymes CD39 and CD73, leading to a surge in extracellular ADO. This increase in adenosine, in turn, helps to sustain an immunosuppressive environment within the tumor. Note: this illustration does not depict the anatomical structure of the tumor, but rather represents the phenomena occurring at different levels of tumor oxygenation. ADO: Adenosine; A2BR: A2B receptors; NK: natural killer; TAM: tumor-associated macrophage; TME: tumor microenvironment; Tregs: regulatory T cells.

Figure 4

Adenosine receptors. Adenosine interacts with four distinct receptors - A1R, A2AR, A2BR, and A3R. Each of these receptors is linked to a G protein-coupled receptor. The A1R and A3R couple with the Gi protein to inhibit Adenylyl Cyclase. In contrast, the G protein coupled to A2AR and A2BR activates Adenylyl Cyclase, leading to an increased formation of intracellular cyclic AMP. A2BRs also couple to Gq which mobilizes Ca²⁺ upon activation. AMP: Adenosine monophosphate; A2AR: A2A receptors; A2BR: A2B receptors; cAMP: cyclic adenosine monophospha.