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β2 adrenergic receptor–mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells
Hemn Mohammadpour, … , Scott I. Abrams, Elizabeth A. Repasky
Hemn Mohammadpour, … , Scott I. Abrams, Elizabeth A. Repasky
Published September 30, 2019
Citation Information: J Clin Invest. 2019;129(12):5537-5552. https://doi.org/10.1172/JCI129502.
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Research Article Immunology Oncology

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

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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 (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.

Authors

Hemn Mohammadpour, Cameron R. MacDonald, Guanxi Qiao, Minhui Chen, Bowen Dong, Bonnie L. Hylander, Philip L. McCarthy, Scott I. Abrams, Elizabeth A. Repasky

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Figure 2

β2-AR activation during chronic stress increases MDSC accumulation in the spleen and tumor.

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β2-AR activation during chronic stress increases MDSC accumulation in th...
(A) Representative flow cytometry analysis of PMN-MDSC and M-MDSC subpopulations, as well as absolute number of PMN-MDSCs and M-MDSCs in tumor and spleen of 4T1 tumor–bearing mice on day 25 after tumor injection. The data presented are from groups of 10 mice from 2 replicate studies. (B) Absolute number of G-MDSCs and M-MDSCs in tumor and spleen of healthy or tumor-bearing mice (4T1 or AT-3) at day 25 after tumor injection housed in ST or TT. The data presented are from groups of 8 mice from 2 replicate studies. (C) Both representative immunohistochemistry analysis and absolute number of Gr-1– (×20 magnification, scale bars = 100 μm), CD31- (×4 magnification, scale bars: 500 μm) and VEGF-α–positive (×10 magnification, scale bars: 200 μm) cells in 4T1 tumors at day 25 after tumor injection. These data are presented as median ± minimum to maximum from groups of 6 mice from 2 replicate studies. The Student’s t test was used to analyze statistical significance between 2 groups. In all panels, *P < 0.05, **P < 0.01, and ***P < 0.001. A P value less than 0.05 was considered significant.
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