Propranolol induces a favourable shift of anti-tumor immunity in a murine spontaneous model of melanoma
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Ludovic Jean Wrobel1, Lloyd Bod2,3,4, Renée Lengagne2,3,4, Masashi Kato5, Armelle Prévost-Blondel2,3,4,*, Frédérique-Anne Le Gal1,*
1Hôpitaux Universitaires de Genève, Service de Dermatologie, Genève, Switzerland
2Inserm, U1016, Institut Cochin, Paris, France
3CNRS, UMR8104, Paris, France
4Université Paris Descartes, Paris, France
5Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Aichi, Japan
*These authors have contributed equally to this work
Ludovic Jean Wrobel, email: email@example.com
Keywords: melanoma, beta-blocker, norepinephrine, anti-tumor immunity, propranolol
Received: August 19, 2016 Accepted: October 12, 2016 Published: October 24, 2016
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.
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