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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >Dopamine inhibits the function of Gr-1(+)CD115(+) myeloid-derived suppressor cells through D1-like receptors and enhances anti-tumor immunity
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Dopamine inhibits the function of Gr-1(+)CD115(+) myeloid-derived suppressor cells through D1-like receptors and enhances anti-tumor immunity

机译：多巴胺通过类D1受体抑制Gr-1（+）CD115（+）髓样抑制细胞的功能，并增强抗肿瘤免疫力

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MDSCs accumulate in tumor-bearing animals and cancer patients and are a major factor responsible for cancer-induced immunosuppression that limits effective cancer immunotherapy. Strategies aimed at effectively inhibiting the function of MDSCs are expected to enhance host anti-tumor immunity and improve cancer immunotherapy significantly. The neurotransmitter DA has been found to have anti-cancer activity, but the underlying mechanism is poorly understood. In this study, we sought to investigate the therapeutic mechanism and efficacy of DA on the inhibition of cancer development via the regulation of MDSC functions. The regulation of the suppressive function of Gr-1(+)CD115(+) MDSCs by DA was determined by use of murine syngeneic LLC and B16 graft models treated with DA in vivo, as well as Gr-1(+)CD115(+) MDSCs isolated from these model treated with DA ex vivo. Here, we show that Gr-1(+)CD115(+) monocytic MDSCs express D1-like DA receptors. DA dramatically attenuated the inhibitory function of tumor-induced monocytic MDSCs on T cell proliferation and IFN-gamma production via D1-like DA receptors and retarded tumor growth. DA and other D1 receptor agonists inhibited IFN-gamma-induced NO production by MDSCs from tumor-bearing mice and cancer patients. Decreased NO production was, in part, mediated via the suppression of p-ERK and p-JNK. In conclusion, the neurotransmitter DA potently inhibits the suppressive function of MDSC and enhances anti-tumor immunity. Our finding provides a mechanistic basis for the use of DA or D1-like receptor agonists to overcome tumor-induced immunosuppression in cancer immunotherapy.
机译：MDSCs累积在荷瘤动物和癌症患者中，并且是导致癌症诱导的免疫抑制的主要因素，从而限制了有效的癌症免疫治疗。旨在有效抑制MDSCs功能的策略有望增强宿主抗肿瘤免疫力并显着改善癌症免疫疗法。已经发现神经递质DA具有抗癌活性，但是其潜在机理尚不清楚。在这项研究中，我们试图通过调节MDSC功能来研究DA抑制癌症发展的治疗机制和功效。 DA对鼠的同系LLC和B16移植物模型以及体内处理过的DA和Gr-1（+）CD115（+）的抑制作用，决定了DA对Gr-1（+）CD115（+）MDSCs抑制功能的调节。 ）从这些模型中分离得到的MDSC进行离体DA处理。在这里，我们表明，Gr-1（+）CD115（+）单核细胞MDSC表达D1样DA受体。 DA大大减弱了肿瘤诱导的单核MDSC通过T1样DA受体对T细胞增殖和IFN-γ产生的抑制作用，并延缓了肿瘤的生长。 DA和其他D1受体激动剂抑制了MDSCs从荷瘤小鼠和癌症患者体内产生的IFN-γ诱导的NO产生。 NO产生的减少部分是通过抑制p-ERK和p-JNK介导的。总之，神经递质DA可以有效抑制MDSC的抑制功能并增强抗肿瘤免疫力。我们的发现为使用DA或D1样受体激动剂克服癌症免疫疗法中肿瘤诱导的免疫抑制提供了机理基础。

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