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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 3

β2-AR deletion decreases the immune suppressive activity of MDSCs.

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β2-AR deletion decreases the immune suppressive activity of MDSCs.
(A) R...
(A) Representative flow cytometry data of the expression of arginase I and PDL-1 plus the percentage of arginase I and PD-L1 in MDSCs derived from bone marrow in the presence of IL-6 and GM-CSF (WT), IL-6, GM-CSF and ISO (WT + ISO) or IL-6, GM-CSF, and ISO and Prop (WT + ISO + Prop) for 6 days. (B) T cells cocultured with WT or WT + ISO MDSCs in various ratios (n = 3). (C) Nanostring nCounter microarray analysis of WT or β2-AR–/– MDSCs sorted by flow cytometry from 4T1 tumors of WT or β2-AR–/– mice 25 days after tumor injection (WT or β2-AR–/– MDSCs were pooled from 5 mice per group). (D) WT and β2-AR–/– MDSCs were sorted from bone marrow of 4T1 tumor–bearing mice, cultured with LPS for 24 hours, and cytokines levels were analyzed in culture media using multiplex (n = 3). (E) Tumor growth kinetics in WT mice orthotopically injected with 4T1 cells (black square) or coinjected with 4T1 cells and WT MDSCs (blue circle) or 4T1 cells and β2-AR–/– MDSCs (red square). MDSCs were sorted from the BM of tumor-bearing mice using an MDSC isolation kit. (F) Tumor growth kinetics in WT or β2-AR–/– mice receiving i.v. transfer (3 × 106 on days 3 and 6 after 4T1 injection) of MDSCs sorted the BM of tumor-bearing WT or β2-AR–/– mice. Two-way ANOVA was used to analyze statistical significance among tumor growth in different groups. These data are presented as mean ± SEM. Other data are presented as median ± minimum to maximum. One-way ANOVA was used to analyze statistical significance among 3 groups, and the Student’s t test was used to analyze statistical significance between 2 groups. In all panels, *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. A P value less than 0.05 was considered significant.

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