Abstract
In a previous study on a xenograft model of melanoma, we showed that the beta-adrenergic receptor antagonist propranolol inhibits melanoma development by modulating angiogenesis, proliferation and cell survival. Stress hormones can influence tumor development in different ways and norepinephrine was shown to downregulate antitumor immune responses by favoring the accumulation of immunosuppressive cells, impairing the function of lymphocytes. We assessed the effect of propranolol on antitumor immune response in the MT/Ret mouse model of melanoma. Propranolol treatment delayed primary tumor growth and metastases development in MT/Ret mice. Consistent with our previous observations in human melanoma xenografts, propranolol induces a decrease in cell proliferation and vessel density in the primary tumors and in metastases. In this immunocompetent model, propranolol significantly reduced the infiltration of myeloid cells, particularly neutrophils, in the primary tumor. Inversely, cytotoxic tumor infiltrating lymphocytes were more frequent in the tumor stroma of treated mice. In a consistent manner, we observed the same shift in the proportions of infiltrating leukocytes in the metastases of treated mice. Our results suggest that propranolol, by decreasing the infiltration of immunosuppressive myeloid cells in the tumor microenvironment, restores a better control of the tumor by cytotoxic cells.
Highlights
Advances in immunotherapy and chemotherapy improved the handling of metastatic melanoma but the restricted number of responders and the rapid development of resistance limit the scope of these approaches [2,3,4]
In the present study we investigated the regulation of anti-tumor immunity by propranolol in melanoma
We reported in a model of human melanoma xenograft that a daily treatment with propranolol reduces tumor vessel density, and decreases melanoma cells survival and proliferation in vivo [18]
Summary
Advances in immunotherapy and chemotherapy improved the handling of metastatic melanoma but the restricted number of responders and the rapid development of resistance limit the scope of these approaches [2,3,4]. We recently decided to investigate the effect of propranolol, a non-selective beta-blocker, on cancer and on melanoma. Our previous investigations showed a higher efficacy of propranolol over the selective beta-1 adrenoceptor blocker www.impactjournals.com/oncotarget metoprolol in inducing melanoma cell death in vitro [18]. Norepinephrine impairs the cytotoxicity of natural killer (NK) cells [28,29,30], the expansion of memory CD8+ T-cells, and promotes a T-Helper 2 lymphocytic response [31]. These observations suggest that norepinephrine may promote the survival and proliferation of melanoma cells and the angiogenesis, and interferes with tumor immune surveillance
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