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.
