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

Abstract

β-adrenergic receptor (β-AR) signaling, by acting directly on tumor cells and angiogenesis, has been showed to exert pro-tumoral effects. Growing evidence also suggests that β-AR expressed by immune cells affect the associated anti-tumor immune response. However, how and where β-AR signaling impinges the anti-tumor immune response is still unclear. Using a mouse model of vaccine-based immunotherapy, we show here that propranolol, a non-selective β-blocker, strongly improved the efficacy of the vaccine by enhancing the frequency of CD8 + T lymphocytes infiltrating the tumor (TILs).However, propranolol had no obvious effect on the reactivity of CD8 + TILs, a result further strengthened by ex-vivo experiments showing that these cells are insensitive to AR signaling triggered by adrenaline or noradrenaline. In contrast, we show that naive CD8 + T cell activation was strongly inhibited by β-AR signaling and that the beneficial effect of propranolol mainly occurred during their initial priming phase. We also demonstrate that the differential sensitivity of CD8 + TILs and naive CD8 + T cells is related to their activation status since in vitro-activated CD8 + T cells behaved similarly to CD8 + TILs, both exhibiting a down-regulation of the β 2 -AR expression. These results reveal that the initial priming phase of the anti-tumor response in the tumor-draining lymph node is a decisive part of the suppressive effect of β-AR signaling on the CD8 + T-cell response against cancer. These findings provide a rationale for the strategic use of clinically available β-blockers in patients to improve cancer immunotherapies such as anti-cancer vaccination strategies.

Role of adrenergic receptor signalling in neuroimmune communication

“…As adrenergic signalling mostly plays a suppressive role in T cells, adrenergic signalling is well studied in various diseases like cancer and other autoimmune diseases. Propranolol, a β-blocker, has been found to increase vaccine efficacy in a murine model by blocking adrenergic signalling in naïve CD8 + T cells ( Daher et al, 2018 ). It is also demonstrated that inhibition of adrenergic signalling decreases the number of PD-1 in CD8 + T cells and helps in checkpoint inhibition therapy ( Bucsek et al, 2017 ).…”