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 1

β2-AR activation increases tumor growth in a MDSC-dependent manner.

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β2-AR activation increases tumor growth in a MDSC-dependent manner. (A a...
(A and B) Tumor growth in mice bearing 4T1 and AT-3 tumor cells, housed at ST (22°C) or TT (30°C). (C) Tumor growth kinetics in WT and β2-AR–/– mice bearing 4T1 tumor cells. (D) Lethally irradiated WT mice received bone marrow transplants from WT (blue circle) or β2-AR–/– (red square) mice. Lethally irradiated β2-AR–/– mice received bone marrow transplants from WT (purple triangle) or β2-AR–/– (brown triangle) mice. Eight weeks after transplantation, chimeric mice were injected with 4T1 tumor cells and tumor growth was monitored. (E) 4T1 tumor–bearing WT or β2-AR–/– mice were injected with isotype or anti–Gr-1 antibodies (200 μg per mouse, i.p., every 4 days), and tumor growth was monitored. (F) β2-AR expression in MDSCs sorted by MDSC isolation kit from spleen of 4T1 tumor–bearing mice 25 days after tumor injection using Image Stream. (G and H) β2-AR expression in MDSCs sorted from bone marrow of non–tumor bearing mice after culture with IL-6, G-CSF, and LPS (data from 3 independent replicates). (I) The levels of β2-AR in splenic MDSCs from healthy or 4T1 tumor–bearing mice using flow cytometry. Two-way ANOVA was used to analyze statistical significance among tumor growth in different groups. These data are presented as mean ± SEM of 5 mice per group from at least 2 replicate experiments. Other data are presented as median ± minimum to maximum. One-way ANOVA was used to analyze statistical significance among 4 groups, and the Student’s t test was used to analyze statistical significance between 2 groups. In all panels, **P < 0.01, ***P < 0.001 and ****P < 0.0001. A P value less than 0.05 was considered significant.