In a mouse model of vaccine immunotherapy against TC-1 tumors, Daher and Vimeux et al. found that administration of propranolol – a β-adrenergic receptor (β-AR) signaling blocker – during T cell priming improved antitumor efficacy primarily by increasing the frequency of infiltrating CD8+ T cells. Propranolol acted on naive T cells in the TDLN, but not on activated CD8+ TILs, which were largely insensitive to adrenaline and noradrenaline. This differential sensitivity was likely due to downregulation of β2-ARs on T cells upon activation. Clinically available β blockers could be useful as adjuvants in cancer immunotherapy, particularly in vaccination.
beta-adrenergic receptor (beta-AR) signaling exerts pro-tumoral effects by acting directly on tumor cells and angiogenesis. In addition, beta-AR expression on immune cells affects their ability to mount anti-tumor immune responses. However, how beta-AR signaling impinges anti-tumor immune responses is still unclear. Using a mouse model of vaccine-based immunotherapy, we showed that propranolol, a non-selective beta-blocker, strongly improved the efficacy of an anti-tumor STxBE7-vaccine by enhancing the frequency of CD8+ T lymphocytes infiltrating the tumor (TILs). However, propranolol had no effect on the reactivity of CD8+ TILs, a result further strengthened by ex-vivo experiments showing that these cells were insensitive to adrenaline or noradrenaline-induced AR signaling. In contrast, naive CD8+ T-cell activation was strongly inhibited by beta-AR signaling and the beneficial effect of propranolol mainly occurred during CD8+ T-cell priming in the tumor-draining lymph node. We also demonstrated that the differential sensitivity of naive CD8+ T cells and CD8+ TILs to beta-AR signaling was linked to a strong down-regulation of beta2-AR expression related to their activation status, since in vitro-activated CD8+ T cells behaved similarly to CD8+ TILs. These results revealed that beta-AR signaling suppresses the initial priming phase of anti-tumor CD8+ T cell-responses, providing a rationale to use clinically available beta-blockers in patients to improve cancer immunotherapies.
Author Info: (1) Department of Immunology, Inflammation and Infection, Institut Cochin, INSERM U1016, CNRS UMR8104, Universite Paris Descartes. (2) Department of Immunology, Inflammation and In
Author Info: (1) Department of Immunology, Inflammation and Infection, Institut Cochin, INSERM U1016, CNRS UMR8104, Universite Paris Descartes. (2) Department of Immunology, Inflammation and Infection, Institut Cochin, INSERM U1016, CNRS UMR8104, Universite Paris Descartes. (3) Department of Immunology, Inflammation and Infection, Institut Cochin, INSERM U1016, CNRS UMR8104, Universite Paris Descartes. (4) Center for Therapeutic Innovation Oncology Servier, Servier (France). (5) INSERM U1016, Institut Cochin. (6) Aix Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France. (7) Immunology, Institut Cochin. (8) Immunology, Institut Cochin. (9) Immunite, inflammation, infection, Institut Cochin, CNRS UMR 8104, Inserm U1016, Univ Paris Descartes paris Sorbonne Cite. (10) Infection, Immunity, Inflammation, Institut Cochin. (11) Department of Immunology, Inflammation and Infection, Institut Cochin, INSERM U1016, CNRS UMR8104, Universite Paris Descartes vincent.feuillet@inserm.fr.
