beta2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells #MMPMID31566578
Mohammadpour H; MacDonald CR; Qiao G; Chen M; Dong B; Hylander BL; McCarthy PL; Abrams SI; Repasky EA
J Clin Invest 2019[Dec]; 129 (12): 5537-5552 PMID31566578show ga
Catecholamines released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type, including myeloid-derived suppressor cells (MDSCs). Using in vitro systems, murine tumor models in wild-type and genetically modified (beta2-AR-/-) mice, and adoptive transfer approaches, we found that the degree of beta2-AR signaling significantly influences MDSC frequency and survival in tumors and other tissues. It also modulates their expression of immunosuppressive molecules such as arginase-I and PD-L1 and alters their ability to suppress the proliferation of T cells. The regulatory functions of beta2-AR signaling in MDSCs were also found to be dependent upon STAT3 phosphorylation. Moreover, we observed that the beta2-AR-mediated increase in MDSC survival is dependent upon Fas-FasL interactions, and this is consistent with gene expression analyses, which reveal a greater expression of apoptosis-related genes in beta2-AR-/- MDSCs. Our data reveal the potential of beta2-AR signaling to increase the generation of MDSCs from both murine and human peripheral blood cells and that the immunosuppressive function of MDSCs can be mitigated by treatment with beta-AR antagonists, or enhanced by beta-AR agonists. This strongly supports the possibility that reducing stress-induced activation of beta2-ARs could help to overcome immune suppression and enhance the efficacy of immunotherapy and other cancer therapies.
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J+Clin+Invest 2019 ; 129 (12): 5537-5552
