?3 -Adrenoceptor as a potential immuno-suppressor agent in melanoma.
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ABSTRACT: BACKGROUND AND PURPOSE:Stress-related catecholamines have a role in cancer and ?-adrenoceptors; specifically, ?2 -adrenoceptors have been identified as new targets in treating melanoma. Recently, ?3 -adrenoceptors have shown a pleiotropic effect on melanoma micro-environment leading to cancer progression. However, the mechanisms by which ?3 -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 ?3 -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 ?-adrenoceptor blockade on the number and activity of immune cell sub-populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with ?-blockers (propranolol and SR59230A) and specific ?-adrenoceptor siRNAs targeting ?2 - or ?3 -adrenoceptors were used. KEY RESULTS:Only ?3 -, but not ?2 -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 ?3 -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 ?3 -adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes. CONCLUSIONS AND IMPLICATIONS:Our data suggest that ?3 -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.
SUBMITTER: Calvani M
PROVIDER: S-EPMC6592854 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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