Abstract
Background: The regulation of melanoma by noradrenergic signaling has gain attention since pre-clinical and clinical studies suggested a benefit of using beta-blockers to control disease progression. We need to confirm that human melanoma recapitulates the mechanisms described from pre-clinical models. Methods: The sources and targets of norepinephrine in the microenvironment of 20 human melanoma samples was investigated using immunostaining. The effect of an exposure to beta-blockers on immune cell type distribution and expression of immune response markers was assessed with immunostaining on 212 human primary melanoma. A statistical analysis explored the effect of an exposure to beta-blockers on progression free survival, melanoma related survival, and overall survival on the 286 eligible patients. Results: Tumor cells and macrophages may be a source of norepinephrine in melanoma microenvironment. Tumors from patients exposed to wide spectrum beta-blockers recapitulate the increased infiltration of T-lymphocytes and the increased production of granzyme B observed in pre-clinical models. An exposure to beta-blockers is associated with a better outcome in our cohort of melanoma patients. Conclusion: This study shows the association between an exposure to wide spectrum beta-blockers and markers of an effective anti-tumor immune response as well as the protective effect of beta-blockers in human melanoma patients.
Highlights
There is growing evidence that the catecholamine norepinephrine (NE) plays a role in melanoma progression and the associated immune suppression
A first prospective study highlighted the protective effect of an adjuvant treatment with the wide spectrum beta-blocker propranolol against melanoma related death [14] confirming the previous observation in retrospective cohorts [15,16,17]
Eye drops of beta-blockers are known to induce systemic effects [19,20] and our results suggest that the administration route does not affect the protective effects of beta-blockers observed on human melanoma tumors
Summary
There is growing evidence that the catecholamine norepinephrine (NE) plays a role in melanoma progression and the associated immune suppression. In a murine model of melanoma, a daily treatment with the wide spectrum beta-blocker propranolol decreases the fraction of myeloid suppressor cells and increases the fraction of cytotoxic lymphoid cells [3] infiltrating the tumor This strengthens the idea that noradrenergic signaling regulates anti-tumor immune response. The12,sources of norepinephrine, the different receptors involved as well as the local versus systemic regulations induced by catecholamines in human melanomas is still a matter of debate [1,6–. Using a cohort of melanoma patients from our archived tissue bank, we assessed the effect of present study we investigated the expression of norepinephrine and its target receptors in human the exposure to various types of beta-blockers on the local immune pattern and melanoma melanoma tumors. Our findings in melanoma patients who are on a beta-blocker treatment largely recapitulate our previous observations in animal models
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