Adenosine is a potent immune suppressive mediator in the tumor microenvironment. A2b adenosine receptor subtype (A2bR) contributes to adenosine-mediated effects in tumor tissue. The aim of this work was to dissect the mechanism/s through which A2bR induces immune suppression in the tumor tissue, focusing on the relationship between myeloid-derived suppressor cells (MDSCs) and other key mediators in the tumor microenvironment. Methods. Using a melanoma mouse model we performed in vivo and ex vivo experiments to study the molecular and cellular events occurring upon A2bR stimulation. Antibody neutralization or cell depletion experiments were performed to evaluate the functional relevance of mediators or cells, respectively, under investigation. To reinforce the translational relevance of targeting A2bR in cancer experiments with pharmacological blockers of A2bR were conducted. Results. We demonstrated that selective blockade of A2bR, with the antagonist PSB1115, stimulates T cell-mediated immunosurveillance by impairing the influx of MDSCs into the tumor microenvironment, that results in robust antineoplastic effects. These data suggest that A2bR plays a pivotal role in promoting immune suppression in the tumor microenvironment. Accordingly, the percentage of tumor-associated MDSCs, identified as CD11b+Gr1+CD11c- cells, was significantly increased in tumor tissue harvested from mice treated with the A2bR agonist Bay60-6583 compared with controls. Conversely, the levels of TGF- and T regulatory cells (Tregs) were unchanged, suggesting that the pro-tumor activity of A2bR relies on its ability to increase the accumulation of MDSCs and not Tregs within tumor tissues. This effect appears to be selective for CD11b+Gr1+cells, because the number of dendritic cells (DC) or CD11b+Gr1- cells were not significantly altered, suggesting that the maturation of these cells is not affected. Depletion of MDSCs completely reversed the effect induced by Bay60-6583. The MDSCs accumulation within tumor tissue was associated with increased tumor levels of CCL-2, IL-10, VEGF, MMP-9 and IL-23. These factors are critically involved in the MDSCs recruitment to cancer. Moreover MDSCs can themselves produce these pro-angiogenic and inflammatory factors. Administration of PSB1115 significantly reverses immune-suppression in the tumor tissue and limits tumor progression in mice. Conclusions. Therefore targeting A2bR could be a new therapeutic strategy to overcome immune suppression in melanoma tissue.

Targeting adenosine A2b receptor reduces melanoma progression in mice: role of tumor-associated MDSCs

MORELLO, SILVANA;SORRENTINO, CLAUDIA;PINTO, Aldo
2014

Abstract

Adenosine is a potent immune suppressive mediator in the tumor microenvironment. A2b adenosine receptor subtype (A2bR) contributes to adenosine-mediated effects in tumor tissue. The aim of this work was to dissect the mechanism/s through which A2bR induces immune suppression in the tumor tissue, focusing on the relationship between myeloid-derived suppressor cells (MDSCs) and other key mediators in the tumor microenvironment. Methods. Using a melanoma mouse model we performed in vivo and ex vivo experiments to study the molecular and cellular events occurring upon A2bR stimulation. Antibody neutralization or cell depletion experiments were performed to evaluate the functional relevance of mediators or cells, respectively, under investigation. To reinforce the translational relevance of targeting A2bR in cancer experiments with pharmacological blockers of A2bR were conducted. Results. We demonstrated that selective blockade of A2bR, with the antagonist PSB1115, stimulates T cell-mediated immunosurveillance by impairing the influx of MDSCs into the tumor microenvironment, that results in robust antineoplastic effects. These data suggest that A2bR plays a pivotal role in promoting immune suppression in the tumor microenvironment. Accordingly, the percentage of tumor-associated MDSCs, identified as CD11b+Gr1+CD11c- cells, was significantly increased in tumor tissue harvested from mice treated with the A2bR agonist Bay60-6583 compared with controls. Conversely, the levels of TGF- and T regulatory cells (Tregs) were unchanged, suggesting that the pro-tumor activity of A2bR relies on its ability to increase the accumulation of MDSCs and not Tregs within tumor tissues. This effect appears to be selective for CD11b+Gr1+cells, because the number of dendritic cells (DC) or CD11b+Gr1- cells were not significantly altered, suggesting that the maturation of these cells is not affected. Depletion of MDSCs completely reversed the effect induced by Bay60-6583. The MDSCs accumulation within tumor tissue was associated with increased tumor levels of CCL-2, IL-10, VEGF, MMP-9 and IL-23. These factors are critically involved in the MDSCs recruitment to cancer. Moreover MDSCs can themselves produce these pro-angiogenic and inflammatory factors. Administration of PSB1115 significantly reverses immune-suppression in the tumor tissue and limits tumor progression in mice. Conclusions. Therefore targeting A2bR could be a new therapeutic strategy to overcome immune suppression in melanoma tissue.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11386/4673642
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