Adenosine A 2B receptor blockade slows growth of bladder and breast tumors

The accumulation of high levels of adenosine in tumors activates adenosine A 2A and A 2B receptors on immune cells to suppress tumor rejection. We evaluated the effects of intratumor injection of a non‐selective adenosine receptor (AR) antagonist, aminophylline (AMO) and, for the first time, a selective A 2B AR antagonist, ATL801. AMO and ATL801 slowed the growth of MB49 bladder and 4T1 breast tumors in syngeneic mice, and reduced by 85% metastasis of breast cancer cells from mammary fat to lung. Based on receptor deletion experiments, the effect of AMO injection was unexpectedly attributed to A 2B AR and not to A 2A AR blockade. AMO and ATL801 significantly increased tumor levels of IFNγ, the interferon‐inducible CXCR3 ligand, CXCL10, and tumor‐infiltrating CXCR3+ T cells. AMO decreased endothelial cell precursors within tumors. Tumor growth inhibition by AMO or ATL801 was eliminated in CXCR3−/− mice and in RAG1−/− mice that lack mature T cells. Bone marrow chimera experiments demonstrated that CXCR3 and A 2B AR expression on bone marrow cells are required for the anti‐tumor effects of AMO. In RAG1−/− mice A 2B AR blockade enhanced CD86 expression on CD11b‐ DCs. The data suggest that blockade of A 2B ARs enhances DC activation and CXCR3‐dependent anti‐tumor responses.