Propranolol induces a favourable shift of anti-tumor immunity in a murine spontaneous model of melanoma

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.

Blockade of β-adrenergic receptor signaling improves cancer vaccine efficacy through its effect on naive CD8+T-cell priming

“…We found that the major effect of β-AR signaling blockade by propranolol treatment occurred at the CD8 + T-cell response level. Our findings are consistent with recent studies showing that adrenergic signals impaired the anti-tumor CD8 + T-cell response, a phenomenon that may be reversed by β-blocker treatment (26)(27)(28)36). Interestingly, the inhibition of the CD8 + T-cell response by adrenergic signals is not limited to the tumor setting and has also been shown in the context of infection, such as influenza (37).…”

β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy

“…We have previously reported that the incidence of a carcinogen-induced tumor model (3-methylcholanthrene; MCA) is reduced in mice housed at 22°C compared to 30°C (14), suggesting that adrenergic signaling likely plays a role in immune surveillance and immune editing. Using a transgenic rat model of melanoma, Wrobel et al (38) found that propranolol also decreased tumor incidence, reduced the number of myeloid cells, and increased the presence of GzmB + CD8 + T cells in tumors at endpoint.…”

β‐Adrenoceptors as drug targets in melanoma: novel preclinical evidence for a role of β3‐adrenoceptors

“…Conflicting results from different studies concur to demonstrate that the effect of propranolol in reducing melanoma progression in mouse xenografts bearing human melanoma cells is dependent on the specific cell type and the experimental conditions (Wrobel and Le Gal, ; Zhou et al ., ; Kuang et al ., ). Finally, in a murine spontaneous model of melanoma, propranolol delays primary tumour growth and metastasis development by decreasing the infiltration of immunosuppressive cells in the tumour micro‐environment (Wrobel et al ., ).…”