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

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 4

β2-AR prolongs MDSC survival.

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β2-AR prolongs MDSC survival. (A) Fas and FasL expression by MDSCs and T...
(A) Fas and FasL expression by MDSCs and T cells from WT or β2-AR–/– mice from tumor and spleen, respectively (n = 5). (B) Expression of Bcl-2 in intratumoral MDSCs from WT or β2-AR–/– 4T1 tumor–bearing mice (n = 5). (C) Levels of apoptosis in MDSCs from tumor and spleen of WT or β2-AR–/– tumor–bearing mice or WT tumor–bearing mice housed at ST or TT. (D) Schematic diagram of experimental design to compare the survival capability of WT or β2-AR–/– MDSCs. (E) WT (CD45.1) or β2-AR–/– (CD45.2) MDSCs were sorted from bone marrow of AT-3 tumor–bearing mice, mixed in 1:1 ratio, and injected into GFP-positive AT-3 tumor–bearing mice. The percentage of WT (CD45.1) or β2-AR–/– (CD45.2) MDSCs in the live, GFP-negative, CD11b+, and Gr-1+ population on day 3 and day 7 after coinjection were analyzed (4 mice per end point). Data are presented as median ± minimum to maximum. 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.