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Adenosine A 2B receptor blockade slows growth of bladder and breast tumors
Author(s) -
Cekic Caglar,
Sag Duygu,
Linden Joel
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1038.2
Subject(s) - cancer research , adenosine , chemistry , blockade , cxcl10 , adenosine receptor , bone marrow , cd86 , endocrinology , medicine , receptor , t cell , immune system , agonist , immunology , chemokine
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.