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

Abstract

β-Adrenergic receptor (β-AR) signaling exerts protumoral effects by acting directly on tumor cells and angiogenesis. In addition, β-AR expression on immune cells affects their ability to mount antitumor immune responses. However, how β-AR signaling impinges antitumor immune responses is still unclear. Using a mouse model of vaccine-based immunotherapy, we showed that propranolol, a nonselective β-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 <i>ex vivo</i> experiments showing that these cells were insensitive to adrenaline- or noradrenaline-induced AR signaling. In contrast, naïve CD8⁺ T-cell activation was strongly inhibited by β-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 naïve CD8⁺ T cells and CD8⁺ TILs to β-AR signaling was linked to a strong downregulation of β₂-AR expression related to their activation status, since <i>in vitro</i>-activated CD8⁺ T cells behaved similarly to CD8⁺ TILs. These results revealed that β-AR signaling suppresses the initial priming phase of antitumor CD8⁺ T-cell responses, providing a rationale to use clinically available β-blockers in patients to improve cancer immunotherapies.