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 β2-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.
- Abbreviations
- STxB
- nontoxic B subunit of Shiga toxin
- TIL
- tumor-infiltrating lymphocyte
- AR
- adrenergic receptor
- DC
- dendritic cell
- TDLN
- tumor-draining lymph node
- TAM
- tumor-associated macrophage
- PMN
- polymorphonuclear cell
- NK cell
- natural killer cell
- Treg
- regulatory CD4+ T cell
- MDSC
- myeloid derived suppressive cell
- TME
- tumor microenvironment
- PGE2
- prostaglandin E2
- BMDC
- bone marrow derived dendritic cell
- Abs
- antibodies
- PKA
- protein kinase A
Footnotes
↵4 Servier Research Institute, Croissy-sur-Seine, France
Grant Support: This study was supported by the French Ligue Nationale contre le Cancer (V. Feuillet); PhD fellowship from the French Ministry of National Education, Research, and Technology (C. Daher)
The authors have no conflicting financial interests.