Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma.

Abstract

The A2b receptor (A2bR) belongs to the adenosine receptor family. Emerging evidence suggest that A2bR is implicated in tumor progression in some murine tumor models, but the therapeutic potential of targeting A2bR in melanoma has not been examined. This study first shows that melanoma-bearing mice treated with Bay 60-6583, a selective A2bR agonist, had increased melanoma growth. This effect was associated with higher levels of immune regulatory mediators interleukin-10 (IL-10) and monocyte chemoattractant protein 1 (MCP-1) and accumulation of tumor-associated CD11b positive Gr1 positive cells (CD11b(+)Gr1(+)) myeloid-derived suppressor cells (MDSCs). Depletion of CD11b(+)Gr1(+) cells completely reversed the protumor activity of Bay 60-6583. Conversely, pharmacological blockade of A2bR with PSB1115 reversed immune suppression in the tumor microenvironment, leading to a significant melanoma growth delay. PSB1115 treatment reduced both levels of IL-10 and MCP-1 and CD11b(+)Gr1(+) cell number in melanoma lesions. These effects were associated with higher frequency of tumor-infiltrating CD8 positive (CD8(+)) T cells and natural killer T (NKT) cells and increased levels of T helper 1 (Th1)-like cytokines. Adoptive transfer of CD11b(+)Gr1(+) cells abrogated the antitumor activity of PSB1115. These data suggest that the antitumor activity of PSB1115 relies on its ability to lower accumulation of tumor-infiltrating MDSCs and restore an efficient antitumor T cell response. The antitumor effect of PSB1115 was not observed in melanoma-bearing nude mice. Furthermore, PSB1115 enhanced the antitumor efficacy of dacarbazine. These data indicate that A2bR antagonists such as PSB1115 should be investigated as adjuvants in the treatment of melanoma.

• Authors: Raffaella Iannone, Lucio Miele, Piera Maiolino, Aldo Pinto, Silvana Morello
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 15 Issue 12 Pg. 1400-9 (Dec 2013) ISSN: 1476-5586 [Electronic] United States
• PMID: 24403862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-propyl-8-(4-sulfophenyl)xanthine
• Adenosine A2 Receptor Antagonists
• Aminopyridines
• Antineoplastic Agents
• BAY 60-6583
• Ccl2 protein, mouse
• Chemokine CCL2
• IL10 protein, mouse
• Immunosuppressive Agents
• Receptor, Adenosine A2B
• Xanthines
• Interleukin-10
• Dacarbazine

Topics

• Adenosine A2 Receptor Antagonists (pharmacology, therapeutic use)
• Aminopyridines (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Chemokine CCL2 (metabolism)
• Dacarbazine (pharmacology, therapeutic use)
• Drug Screening Assays, Antitumor
• Drug Synergism
• Female
• Immunosuppressive Agents (pharmacology)
• Interleukin-10 (metabolism)
• Melanoma, Experimental (drug therapy, immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Myeloid Cells (drug effects, immunology, transplantation)
• Natural Killer T-Cells (immunology)
• Neoplasm Transplantation
• Receptor, Adenosine A2B (metabolism)
• Tumor Burden (drug effects)
• Tumor Escape
• Tumor Microenvironment
• Xanthines (pharmacology, therapeutic use)