Blockade of β-Adrenergic Receptors Improves CD8+ T-cell Priming and Cancer Vaccine Efficacy

beta-Adrenergic receptor (beta-AR) signaling exerts protumoral effects by acting directly on tumor cells and angiogenesis. In addition, beta-AR expression on immune cells affects their ability to mount antitumor immune responses. However, how beta-AR signaling impinges antitumor immune responses is still unclear. Using a mouse model of vaccine-based immunotherapy, we showed that propranolol, a nonselective beta-blocker, strongly improved the efficacy of an antitumor STxBE7 vaccine by enhancing the frequency of CD8(+) T lymphocytes infiltrating the tumor (TIL). 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 downregulation of beta(2)-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 antitumor CD8(+) T-cell responses, providing a rationale to use clinically available beta-blockers in patients to improve cancer immunotherapies.