β3-Adrenoceptor as a potential immuno-suppressor agent in melanoma

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.