ß2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells.
J Clin Invest
; 129(12): 5537-5552, 2019 12 02.
Article
em En
| MEDLINE
| ID: mdl-31566578
ABSTRACT
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 (ß2-AR-/-) mice, and adoptive transfer approaches, we found that the degree of ß2-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 ß2-AR signaling in MDSCs were also found to be dependent upon STAT3 phosphorylation. Moreover, we observed that the ß2-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 ß2-AR-/- MDSCs. Our data reveal the potential of ß2-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 ß-AR antagonists, or enhanced by ß-AR agonists. This strongly supports the possibility that reducing stress-induced activation of ß2-ARs could help to overcome immune suppression and enhance the efficacy of immunotherapy and other cancer therapies.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores Adrenérgicos beta 2
/
Células Supressoras Mieloides
/
Tolerância Imunológica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2019
Tipo de documento:
Article