β3-Adrenoceptors as Putative Regulator of Immune Tolerance in Cancer and Pregnancy

Abstract

Understanding the mechanisms of immune tolerance is currently one of the most important challenges of scientific research. Pregnancy affects the immune system balance, leading the host to tolerate embryo alloantigens. Previous reports demonstrated that β-adrenergic receptor (β-AR) signaling promotes immune tolerance by modulation of NK and Treg, mainly through the activation of β2-ARs, but recently we have demonstrated that also β3-ARs induce an immune-tolerant phenotype in mice bearing melanoma. In this report, we demonstrate that β3-ARs support host immune tolerance in the maternal microenvironment by modulating the same immune cells populations as recently demonstrated in cancer. Considering that β3-ARs are modulated by oxygen levels, we hypothesize that hypoxia, through the upregulation of β3-AR, promotes the biological shift toward a tolerant immunophenotype and that this is the same trick that embryo and cancer use to create an aura of immune-tolerance in a competent immune environment. This study confirms the analogies between fetal development and tumor progression and suggests that the expression of β3-ARs represents one of the strategies to induce fetal and tumor immune tolerance.

Effect of Beta 3 Adrenoreceptor Modulation on Patency of the Ductus Arteriosus

“…These hypotheses are not mutually exclusive and provide background to further pharmacological investigations on SR59230A to better elucidate its effects and underlying mechanisms of action. In addition to the above points, a recent study has shown that β3-AR is involved in the mechanisms of fetal immune tolerance [44]. Hence, it cannot be ruled out that β3-AR blockade by SR59230A may have increased the occurrence of abortion through an immune-mediated mechanism, although this is unlikely because of the very late stage of pregnancy at the time of drug delivery.…”

Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments

“…The activation of α1-AR leads to the increase of intracellular calcium concentration via the PLC-IP3/DAG pathway, while the activation of α2-AR results in the inhibition of adenylyl cyclase, which decreases the concentration of cytoplasmic calcium and cAMP (Biazi et al, 2018;Durkee et al, 2019) (Figure 2). β-ARs are expressed on the membranes of various tumor cells and tumor-related cells, such as immune cells, fibroblast, and epithelial cells, and epithelial cells, and two of the three subtypes of β-ARs, including β2-AR and β3-AR, take part in tumorous β-signaling (Daly and McGrath, 2011;Calvani et al, 2020). The binding of catecholamine, like epinephrine and norepinephrine, to β-ARs, contributes to the activation of guanylate cyclase, leading to transient cyclic adenosine monophosphate (cAMP) flux, which subsequently activates protein kinase A (PKA) and guanine nucleotide exchange protein activated by adenylyl cyclase (EPAC) (Cole and Sood, 2012).…”

β3‐Adrenoceptor, a novel player in the round‐trip from neonatal diseases to cancer: Suggestive clues from embryo

“…A similar phenomenon was observed in the decidua where maternal β3-AR blockade induced a surge of immune-competent CD8 cells, concomitant with a reduction of immune tolerant decidual NK cells, indicating that β3-ARs might guarantee a halo of immune tolerance within the fetal-maternal interface by modulating the same immune cells as in cancer. 156 Globally, these results suggest the possibility that hypoxia may promote the biological shift towards a tolerant immunophenotype through the upregulation of β3-ARs, and that this trick may be used by both embryo and cancer to create an aura of immune tolerance in a previous immune-competent environment. In this light, the cancer microenvironment may be considered a sort of "tumor placenta" and cancer as a disease that exploits the same tricks allowing the embryo to grow, by reactivating fetal competences through the intervention of β3-ARs.…”

“…155 In a second study, the role of β3-ARs in the maintenance of prenatal immune tolerance was investigated. 156 In pregnant mice, β3-AR blockade increased the number and the cytotoxicity of NK cells, while attenuating the infiltration of MDSCs and Treg cells in the mouse placenta. A similar phenomenon was observed in the decidua where maternal β3-AR blockade induced a surge of immune-competent CD8 cells, concomitant with a reduction of immune tolerant decidual NK cells, indicating that β3-ARs might guarantee a halo of immune tolerance within the fetal-maternal interface by modulating the same immune cells as in cancer.…”

“…In a second study, the role of β3‐ARs in the maintenance of prenatal immune tolerance was investigated 156 . In pregnant mice, β3‐AR blockade increased the number and the cytotoxicity of NK cells, while attenuating the infiltration of MDSCs and Treg cells in the mouse placenta.…”