Adrenergic Signaling in Immunotherapy of Cancer: Friend or Foe?

Abstract

The incidence of cancer is increasing worldwide, which is to a large extent related to the population’s increasing lifespan. However, lifestyle changes in the Western world are causative as well. Exercise is intrinsically associated with what one could call a “healthy life”, and physical activity is associated with a lower risk of various types of cancer. Mouse models of exercise have shown therapeutic efficacy across numerous cancer models, at least in part due to the secretion of adrenaline, which mobilizes cells of the immune system, i.e., cytotoxic T and natural killer (NK) cells, through signaling of the β-2 adrenergic receptor (β2AR). Clinical trials aiming to investigate the clinical value of exercise are ongoing. Strikingly, however, the use of β-blockers—antagonists of the very same signaling pathway—also shows signs of clinical potential in cancer therapy. Cancer cells also express β-adrenergic receptors (βARs) and signaling of the receptor is oncogenic. Moreover, there are data to suggest that β2AR signaling in T cells renders the cell functionally suppressed. In this paper, we discuss these seemingly opposing mechanisms of cancer therapy—exercise, which leads to increased β2AR signaling, and β-blocker treatment, which antagonizes that same signaling—and suggest potential mechanisms and possibilities for their combination.

The effect of concomitant use of statins, NSAIDs, low-dose aspirin, metformin and beta-blockers on outcomes in patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis

“…Increasing evidence suggests that beta-adrenergic signaling has been shown to influence the genesis and progression of multiple tumors and to intertwine with immune cells (e.g., CD8 + T cells, regulatory T cells, myeloid-derived suppressor cells). 41 , 42 Nevertheless, all eligible studies reported no significant association between the concomitant use of beta-blockers and OS and PFS in the multivariate analysis. Cortellini et al 18 reported that beta-blockers are significantly associated with a favorable objective response rate in the multivariate analysis.…”

ADRB2 is a potential protective gene in breast cancer by regulating tumor immune microenvironment

“…For centuries, a large number of studies had suggested that somatic and psychosocial factors may significantly affect cancer development ( 11 , 13 , 14 , 17 , 18 ). However, the underlying mechanisms of psychosocial factors were still not elucidated with more detail.…”

“…The gene ADRB2 encodes β2-AR, which is a member of the G protein-coupled receptor superfamily ( 11 , 17 ). It was reported that the two ligands—adrenaline and noradrenaline bind to β-ARs with different affinity, noradrenaline has a higher affinity to β1-AR, and adrenaline to β2-AR ( 13 , 18 ).…”

“…As vasoactive drugs, β-ARs agonists are conventionally used for regulating blood pressure cancer patients during anesthetic management. However, it has been shown that β-ARs signaling exerted dual effects in cancers ( 13 , 18 ). Chronic stress led to upregulated MDSCs and Tregs, resulting in immune-suppressive effect, while acute stress and exercise which largely rely on ADRB2 can probably inhibit tumor growth, by leading to an increase of immune cells infiltration in TME.…”

Effects of Serum From Radiofrequency Ablation Patients Receiving General Anesthesia or Local Anesthesia on Hepatocellular Carcinoma Cancer Cell Malignancy: A Prospective Randomized Controlled Trial

“…The most obvious change induced by the GA technique is a loss of state of consciousness. In an awake patient, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, whose activation is widely accepted to be associated with immune suppression ( 36 , 37 ), should be more highly activated than in an anesthetized patient. Therefore, from this point of view, GA should have resulted in a better prognosis for cancer patients compared to patients receiving LA, which seems contradictory to the current findings.…”