Background: Adenosine is an ATP metabolite, generated in the extracellular space by the ectonucleotidase CD73. In the tumor microenvironment adenosine impairs anti-tumor immunity, through the Gs-coupled receptors A2A and/or A2B, promoting tumor growth and survival. Blockade of CD73 or A2AR subtype has been shown to improve the anti-tumor immune response. Inhibitors of these targets are currently in Phase I clinical trials in cancer patients. Whilst A2AR is the most thoroughly characterized receptor involved in the immunosuppressive effects of adenosine, A2B is emerging as a potential anti-cancer target. Materials and methods: To investigate the mechanisms through which the A2BR pharmacological modulators impact the primary tumor growth a syngeneic mouse model of melanoma was used. B16.F10 melanoma-bearing mice were treated with a selective antagonist of A2BR, PSB1115. Myeloid and lymphoid leucocyte populations were analyzed in the tumor tissue, tumor draining lymph node and spleen harvested from control and PSB1115-treated groups. The effects of A2BR modulators were also examined in tumor stroma cells, including endothelial cells and melanoma-associated fibroblasts. The therapeutic potential of the A2BR blocker was tested in combination with some chemotherapeutics, such as dacarbazine. Results: Our results show that A2BR inhibition with PSB1115 significantly delayed tumor growth in mice. PSB1115 treatment decreased the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment but not in non-tumoral peripheral organs. This effect was associated with an increased numbers of tumor-infiltrating CD8+ T cells and NKT cells, and enhanced levels of IFN-γ and granzyme B. The anti-tumor effects of PSB1115 was indeed lost in melanoma-bearing nude mice lacking of T cells. The effects of A2BR inhibitor was also evaluated on tumor stroma cells. Tumor angiogenesis in PSB1115-treated mice was inhibited and the expression levels of tumor VEGF reduced. Furthermore we found that PSB1115 treatment impacted the function of melanoma-associated fibroblasts in producing FGF2 and CXCL12, which contribute to enhance tumor growth. Treatment of animals with PSB1115 enhanced the anti-tumor activity of dacarbazine and anti-VEGF agents. Conclusions: Pharmacological blockade of A2BR inhibits the growth of syngeneic melanoma in vivo. PSB1115 treatment decreases the number of tumor MDSCs, increases the number of tumor-infiltrating T lymphocytes, affects tumor angiogenesis and the activation of melanoma-associated fibroblasts. Therefore data from animal studies support the therapeutic potential of A2B blockers in melanoma.

The A2B adenosine receptor: an emerging therapeutic target in cancer

Morello Silvana
;
Claudia Sorrentino;Aldo Pinto
2017

Abstract

Background: Adenosine is an ATP metabolite, generated in the extracellular space by the ectonucleotidase CD73. In the tumor microenvironment adenosine impairs anti-tumor immunity, through the Gs-coupled receptors A2A and/or A2B, promoting tumor growth and survival. Blockade of CD73 or A2AR subtype has been shown to improve the anti-tumor immune response. Inhibitors of these targets are currently in Phase I clinical trials in cancer patients. Whilst A2AR is the most thoroughly characterized receptor involved in the immunosuppressive effects of adenosine, A2B is emerging as a potential anti-cancer target. Materials and methods: To investigate the mechanisms through which the A2BR pharmacological modulators impact the primary tumor growth a syngeneic mouse model of melanoma was used. B16.F10 melanoma-bearing mice were treated with a selective antagonist of A2BR, PSB1115. Myeloid and lymphoid leucocyte populations were analyzed in the tumor tissue, tumor draining lymph node and spleen harvested from control and PSB1115-treated groups. The effects of A2BR modulators were also examined in tumor stroma cells, including endothelial cells and melanoma-associated fibroblasts. The therapeutic potential of the A2BR blocker was tested in combination with some chemotherapeutics, such as dacarbazine. Results: Our results show that A2BR inhibition with PSB1115 significantly delayed tumor growth in mice. PSB1115 treatment decreased the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment but not in non-tumoral peripheral organs. This effect was associated with an increased numbers of tumor-infiltrating CD8+ T cells and NKT cells, and enhanced levels of IFN-γ and granzyme B. The anti-tumor effects of PSB1115 was indeed lost in melanoma-bearing nude mice lacking of T cells. The effects of A2BR inhibitor was also evaluated on tumor stroma cells. Tumor angiogenesis in PSB1115-treated mice was inhibited and the expression levels of tumor VEGF reduced. Furthermore we found that PSB1115 treatment impacted the function of melanoma-associated fibroblasts in producing FGF2 and CXCL12, which contribute to enhance tumor growth. Treatment of animals with PSB1115 enhanced the anti-tumor activity of dacarbazine and anti-VEGF agents. Conclusions: Pharmacological blockade of A2BR inhibits the growth of syngeneic melanoma in vivo. PSB1115 treatment decreases the number of tumor MDSCs, increases the number of tumor-infiltrating T lymphocytes, affects tumor angiogenesis and the activation of melanoma-associated fibroblasts. Therefore data from animal studies support the therapeutic potential of A2B blockers in melanoma.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11386/4704503
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