Maura Calvani1, Gennaro Bruno2, Massimo Dal Monte3, Romina Nassini2, Filippo Fontani2, Arianna Casini4, Lorenzo Cavallini5, Matteo Becatti6, Francesca Bianchini6, Francesco De Logu2, Giulia Forni7, Giancarlo la Marca7, Lido Calorini6, Paola Bagnoli3, Paola Chiarugi6, Alberto Pupi6, Chiara Azzari2, Pierangelo Geppetti2, Claudio Favre1, Luca Filippi8. 1. Oncohematology Unit, Department of Pediatric Oncology, Meyer University Children's University Hospital, Florence, Italy. 2. Department of Health Sciences, University of Florence, Florence, Italy. 3. Department of Biology, Unit of General Physiology, University of Pisa, Pisa, Italy. 4. Division of Immunology, Section of Pediatrics, Meyer University Children's Hospital, Florence, Italy. 5. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. 6. Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy. 7. Metabolic and Newborn Screening Clinical Unit, Department of Neurosciences, Meyer University Children's University Hospital, Florence, Italy. 8. Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, Meyer University Children's Hospital, Florence, Italy.
Abstract
BACKGROUND AND PURPOSE: Stress-related catecholamines have a role in cancer and β-adrenoceptors; specifically, β2 -adrenoceptors have been identified as new targets in treating melanoma. Recently, β3 -adrenoceptors have shown a pleiotropic effect on melanoma micro-environment leading to cancer progression. However, the mechanisms by which β3 -adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub-population homeostasis. Understanding the mechanisms of cancer immune-tolerance is one of the most intriguing challenges in modern research. This study investigates the potential role of β3 -adrenoceptors in immune-tolerance regulation. EXPERIMENTAL APPROACH: A mouse model of melanoma in which syngeneic B16-F10 cells were injected in C57BL-6 mice was used to evaluate the effect of β-adrenoceptor blockade on the number and activity of immune cell sub-populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with β-blockers (propranolol and SR59230A) and specific β-adrenoceptor siRNAs targeting β2 - or β3 -adrenoceptors were used. KEY RESULTS: Only β3 -, but not β2 -adrenoceptors, were up-regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub-populations including Treg, MDSC, and NK. SR59230A and β3 -adrenoceptor siRNAs increased NK and CD8 number and cytotoxicity, while they attenuated Treg and MDSC sub-populations in the tumour mass, blood, and spleen. SR59230A and β3 -adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes. CONCLUSIONS AND IMPLICATIONS: Our data suggest that β3 -adrenoceptors are involved in immune-tolerance, which opens the way for new strategic therapies to overcome melanoma growth. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
BACKGROUND AND PURPOSE:Stress-related catecholamines have a role in cancer and β-adrenoceptors; specifically, β2 -adrenoceptors have been identified as new targets in treating melanoma. Recently, β3 -adrenoceptors have shown a pleiotropic effect on melanoma micro-environment leading to cancer progression. However, the mechanisms by which β3 -adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub-population homeostasis. Understanding the mechanisms of cancer immune-tolerance is one of the most intriguing challenges in modern research. This study investigates the potential role of β3 -adrenoceptors in immune-tolerance regulation. EXPERIMENTAL APPROACH: A mouse model of melanoma in which syngeneic B16-F10 cells were injected in C57BL-6 mice was used to evaluate the effect of β-adrenoceptor blockade on the number and activity of immune cell sub-populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with β-blockers (propranolol and SR59230A) and specific β-adrenoceptor siRNAs targeting β2 - or β3 -adrenoceptors were used. KEY RESULTS: Only β3 -, but not β2 -adrenoceptors, were up-regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub-populations including Treg, MDSC, and NK. SR59230A and β3 -adrenoceptor siRNAs increased NK and CD8 number and cytotoxicity, while they attenuated Treg and MDSC sub-populations in the tumour mass, blood, and spleen. SR59230A and β3 -adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes. CONCLUSIONS AND IMPLICATIONS: Our data suggest that β3 -adrenoceptors are involved in immune-tolerance, which opens the way for new strategic therapies to overcome melanoma growth. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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