β2 adrenergic receptor–mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells

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 (β2-AR-/-) mice, and adoptive transfer approaches,...

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Vydáno v:The Journal of clinical investigation Ročník 129; číslo 12; s. 5537 - 5552
Hlavní autoři: Mohammadpour, Hemn, MacDonald, Cameron R., Qiao, Guanxi, Chen, Minhui, Dong, Bowen, Hylander, Bonnie L., McCarthy, Philip L., Abrams, Scott I., Repasky, Elizabeth A.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States American Society for Clinical Investigation 02.12.2019
Témata:
Animals
Immune Tolerance
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Myeloid-Derived Suppressor Cells - immunology
Myeloid-Derived Suppressor Cells - physiology
Neoplasms - blood supply
Phosphorylation
Receptors, Adrenergic, beta-2 - immunology
Signal Transduction - physiology
STAT3 Transcription Factor - metabolism
Oncology
Immunology
G-protein coupled receptors
Cancer immunotherapy
Cellular immune response
ISSN:0021-9738, 1558-8238, 1558-8238
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Shrnutí: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 (β2-AR-/-) mice, and adoptive transfer approaches, we found that the degree of β2-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 β2-AR signaling in MDSCs were also found to be dependent upon STAT3 phosphorylation. Moreover, we observed that the β2-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 β2-AR-/- MDSCs. Our data reveal the potential of β2-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 β-AR antagonists, or enhanced by β-AR agonists. This strongly supports the possibility that reducing stress-induced activation of β2-ARs could help to overcome immune suppression and enhance the efficacy of immunotherapy and other cancer therapies.
Bibliografie:ObjectType-Article-1
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ISSN:0021-9738
1558-8238
1558-8238
DOI:10.1172/JCI129502