β2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells
β2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells
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DOI：
10.1172/jci129502
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发表时间：
2019-12-02
影响因子：
15.9
通讯作者：
Repasky, Elizabeth A.
中科院分区：
文献类型：
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作者：
Mohammadpour, Hemn;MacDonald, Cameron R.;Repasky, Elizabeth A.
交感神经释放的儿茶酚胺可以激活几乎所有细胞类型上存在的肾上腺素能受体，包括骨髓源性抑制细胞 (MDSC)。使用体外系统、野生型和转基因 (β 2-AR(-/-)) 小鼠的鼠肿瘤模型以及过继转移方法，我们发现 β 2-AR 信号传导程度显着影响肿瘤和其他组织中的 MDSC 频率和存活率。它还调节精氨酸酶-I 和 PD-L1 等免疫抑制分子的表达，并改变它们抑制 T 细胞增殖的能力。还发现 MDSC 中 β2-AR 信号传导的调节功能依赖于 STAT3 磷酸化。此外，我们观察到β2-AR介导的MDSC存活率增加依赖于Fas-FasL相互作用，这与基因表达分析一致，基因表达分析揭示了β2-AR(-/-)MDSC中凋亡相关基因的表达更高。我们的数据揭示了β2-AR信号传导增加小鼠和人类外周血细胞MDSC生成的潜力，并且MDSC的免疫抑制功能可以通过β-AR拮抗剂治疗减轻，或通过β-AR激动剂增强。这有力地证明了减少应激诱导的 β2-AR 激活可能有助于克服免疫抑制并增强免疫疗法和其他癌症疗法疗效的可能性。
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 (beta 2-AR(-/-)) mice, and adoptive transfer approaches, we found that the degree of beta 2-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 beta 2-AR signaling in MDSCs were also found to be dependent upon STAT3 phosphorylation. Moreover, we observed that the beta 2-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 beta 2-AR(-/-) MDSCs. Our data reveal the potential of beta 2-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 beta-AR antagonists, or enhanced by beta-AR agonists. This strongly supports the possibility that reducing stress-induced activation of beta 2-ARs could help to overcome immune suppression and enhance the efficacy of immunotherapy and other cancer therapies.