Propranolol Attenuates Surgical Stress–Induced Elevation of the Regulatory T Cell Response in Patients Undergoing Radical Mastectomy

Abstract

Surgical stress and inflammatory response induce the release of catecholamines and PGs, which may be key factors in facilitating cancer recurrence through immunosuppression. Animal studies have suggested the efficacy of perioperative blockades of catecholamines and PGs in reducing immunosuppression. In this study, to our knowledge, we present the first report of the effects of perioperative propranolol and/or parecoxib on peripheral regulatory T cells (Tregs) in breast cancer patients. Patients were randomly assigned to control, propranolol, parecoxib, and propranolol plus parecoxib groups. We demonstrated that levels of circulating epinephrine, norepinephrine, and PGE2 increased in response to surgery. Meanwhile, peripheral FOXP3 mRNA level and Treg frequencies were elevated on postoperative day 7. Propranolol administration, rather than parecoxib, attenuated such elevation of Tregs, indicating the critical roles for catecholamines in surgery-induced promotion of Tregs. Besides, propranolol plus parecoxib treatment demonstrated no additive or synergistic effects. Furthermore, a study of Treg activity on CD4+ T cell responses to specific tumor Ags was performed in the control and propranolol groups. Propranolol abrogated the increased Treg activity and accompanying suppression of CD4+ T cell responses after surgery. Finally, we conducted ex vivo experiments on the effects of varying concentrations of epinephrine and/or propranolol on Treg proliferation over PBMCs from breast cancer patients, to provide further direct evidence strengthening our clinical observations. Epinephrine markedly promoted Treg proliferation, whereas propranolol prevented such enhancement effect. In conclusion, our study highlights beneficial roles for propranolol in inhibiting Treg responses in vivo and in vitro, and demonstrates that propranolol could alleviate surgical stress–induced elevation of Tregs in breast cancer patients.

β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms

“…Notably, there is a large discrepancy of drug concentration between in vitro and in vivo models. This may be because propranolol inhibits the growth of the tumor itself in vivo, and also inhibits angiogenesis (38) and regulates immune system function (39,40). This multifaceted antitumor effect may be beneficial in decreasing the drug concentration in in vivo models.…”

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

“…Zhou et al studied the impact of PRO and the COX-2 inhibitor parecoxib on T-reg numbers in breast cancer patients undergoing radical mastectomy [161]. Patients were assigned to control, PRO, parecoxib and PRO + parecoxib groups.…”

Cytomegalovirus serostatus, inflammation, and antibody response to influenza vaccination in older adults: The moderating effect of beta blockade

“…The availability of pre-clinical data and approved, safe, and inexpensive beta-antagonists with well-understood pharmacology and minimal side effects provide a favorable risk/benefit profile for clinical testing of beta blockade (Baker, Hill, & Summers, 2011). Previous experimental designs have tested shorter-term beta blockade (in patients without confounding indication of cardiovascular issues) as an effective therapeutic in, for example, clinical oncology for cancer cachexia and immune outcomes in the perioperative period of breast cancer surgery (Stewart Coats et al, 2016; Zhou et al, 2016). …”