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

Abstract

b-Adrenergic receptor (b-AR) signaling exerts protumoral effects by acting directly on tumor cells and angiogenesis. In addition, bAR expression on immune cells affects their ability to mount antitumor immune responses. However, how bAR signaling impinges antitumor immune responses is still unclear. Using a mouse model of vaccine-based immunotherapy, we showed that propranolol, a nonselective b-blocker, strongly improved the efficacy of an antitumor STxBE7 vaccine by enhancing the frequency of CD8 þ T lymphocytes infiltrating the tumor (TIL). However, propranolol had no effect on the reactivity of CD8 þ TILs, a result further strengthened by ex vivo experiments showing that these cells were insensitive to adrenaline-or noradrenaline-induced AR signaling. In contrast, na€ ve CD8 þ T-cell activation was strongly inhibited by bAR signaling, and the beneficial effect of propranolol mainly occurred during CD8 þ T-cell priming in the tumor-draining lymph node. We also demonstrated that the differential sensitivity of na€ ve CD8 þ T cells and CD8 þ TILs to bAR signaling was linked to a strong downregulation of b 2-AR expression related to their activation status, since in vitro-activated CD8 þ T cells behaved similarly to CD8 þ TILs. These results revealed that bAR signaling suppresses the initial priming phase of antitumor CD8 þ T-cell responses, providing a rationale to use clinically available b-blockers in patients to improve cancer immunotherapies.

Propranolol Suppresses the Growth of Colorectal Cancer Through Simultaneously Activating Autologous CD8+ T Cells and Inhibiting Tumor AKT/MAPK Pathway

“…15 They do not come singly but in pairs, signaling through ß2-AR negatively regulates CD8 + T cell's priming. 33 Interestingly, we also found a significantly decreased ratio of FoxP3 + in CD4 + T cells. The CD4 + FoxP3 + Treg cells are thought to play an important role in antitumor immune response.…”

T cell receptor therapy against melanoma—Immunotherapy for the future?

“…Case‐control studies from the UK, the Netherlands and the United States could also not show beneficial effect in melanoma patients receiving ICI therapy 171–173 . A recent study in a murine melanoma model showed enhanced effect of vaccine in combination with β‐blockers due to a direct effect of β‐blockers on naïve CD8+ T cells which have high levels of β‐AR 174 . In contrast to mice, human memory CD8+ T cells express higher levels of β‐AR than naïve CD8+ T cells 175 .…”

The Relationship Between Anti-Hypertensive Drugs and Cancer: Anxiety to be Resolved in Urgent

“…The studies by Xie et al (Xie et al, 2019), Montoya et al (Montoya et al, 2019), and Maiko et al (Sasaki et al, 2019) showed that BBs inhibited the occurrence and development of cancer by regulating gene expressions. Daher et al (Daher et al, 2019) and Inderberg et al (Inderberg and Wälchli, 2020) also found that BBs regulated the effect of inflammation on tumors. In general, BBs, such as ACEIs/ARBs, regulate their occurrence and development through multiple channels; nonetheless, more mechanisms will be discovered in the future.…”