Blockade of β-Adrenergic Receptors Improves CD8+ T-cell Priming and Cancer Vaccine Efficacy.
Clara DaherLene VimeuxRalitsa StoevaElisa PeranzoniGeorges BismuthElisabeth WieduwildBruno LucasEmmanuel DonnadieuNadège BercoviciAlain TrautmannVincent FeuilletPublished in: Cancer immunology research (2019)
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 ex vivo 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 in vitro-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.
Keyphrases
- immune response
- lymph node
- mouse model
- poor prognosis
- signaling pathway
- ejection fraction
- magnetic resonance
- magnetic resonance imaging
- induced apoptosis
- clinical trial
- cell proliferation
- oxidative stress
- squamous cell carcinoma
- toll like receptor
- early stage
- prognostic factors
- endoplasmic reticulum stress
- single cell
- binding protein
- sentinel lymph node
- patient reported outcomes