Adenosine A2B receptor blockade slows growth of bladder and breast tumors.

Abstract

The accumulation of high levels of adenosine in tumors activates A(2A) and A(2B) receptors on immune cells and inhibits their ability to suppress tumor growth. Deletion of adenosine A(2A) receptors (A(2A)ARs) has been reported to activate antitumor T cells, stimulate dendritic cell (DC) function, and inhibit angiogenesis. In this study, we evaluated the effects of intermittent intratumor injection of a nonselective adenosine receptor antagonist, aminophylline (AMO; theophylline ethylenediamine) and, for the first time to our knowledge, 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% metastasizes of breast cancer cells from mammary fat to lung. Based on experiments with A(2A)AR(-/-) or adenosine A(2B) receptor(-/-) mice, 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 IFN-γ and the IFN-inducible chemokine CXCL10, which is a ligand for CXCR3. This was associated with an increase in activated tumor-infiltrating CXCR3(+) T cells and a decrease in endothelial cell precursors within tumors. Tumor growth inhibition by AMO or ATL801 was eliminated in CXCR3(-/-) mice and RAG1(-/-) mice that lack mature T cells. In RAG1(-/-) mice, A(2B)AR deletion enhanced CD86 expression on CD11b(-) DCs. Bone marrow chimera experiments demonstrated that CXCR3 and A(2B)AR expression on bone marrow cells is required for the antitumor effects of AMO. The data suggest that blockade of A(2B)ARs enhances DC activation and CXCR3-dependent antitumor responses.

• Authors: Caglar Cekic, Duygu Sag, Yuesheng Li, Dan Theodorescu, Robert M Strieter, Joel Linden
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 188 Issue 1 Pg. 198-205 (Jan 01 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 22116822 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adenosine A2 Receptor Antagonists
• B7-2 Antigen
• Cd86 protein, mouse
• Chemokine CXCL10
• Cxcl10 protein, mouse
• Cxcr3 protein, mouse
• Homeodomain Proteins
• Receptor, Adenosine A2B
• Receptors, CXCR3
• RAG-1 protein
• Interferon-gamma

Topics

• Adenosine A2 Receptor Antagonists (pharmacology)
• Animals
• B7-2 Antigen (genetics, immunology, metabolism)
• Bone Marrow Cells (immunology, metabolism, pathology)
• Bone Marrow Transplantation
• Cell Line, Tumor
• Chemokine CXCL10 (genetics, immunology, metabolism)
• Dendritic Cells (immunology, metabolism, pathology)
• Female
• Homeodomain Proteins (genetics, immunology, metabolism)
• Interferon-gamma (genetics, immunology, metabolism)
• Mammary Neoplasms, Animal (drug therapy, genetics, immunology, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Neoplasm Transplantation
• Receptor, Adenosine A2B (genetics, immunology, metabolism)
• Receptors, CXCR3 (genetics, immunology, metabolism)
• Transplantation Chimera (genetics, immunology, metabolism)
• Transplantation, Isogeneic
• Urinary Bladder Neoplasms (drug therapy, genetics, immunology, metabolism, pathology)