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

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 beta-adrenergic receptor (beta-AR) signaling promotes immune tolerance by modulation of NK and Treg, mainly through the activation of beta 2-ARs, but recently we have demonstrated that also beta 3-ARs induce an immune-tolerant phenotype in mice bearing melanoma. In this report, we demonstrate that beta 3-ARs support host immune tolerance in the maternal microenvironment by modulating the same immune cells populations as recently demonstrated in cancer. Considering that beta 3-ARs are modulated by oxygen levels, we hypothesize that hypoxia, through the upregulation of beta 3-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 beta 3-ARs represents one of the strategies to induce fetal and tumor immune tolerance.