Prim-O-glucosylcimifugin通过靶向髓样来源的抑制细胞来增强PD-1抑制作用的抗肿瘤作用。,Journal for ImmunoTherapy of Cancer

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Prim-O-glucosylcimifugin通过靶向髓样来源的抑制细胞来增强PD-1抑制作用的抗肿瘤作用。
Journal for ImmunoTherapy of Cancer ( IF 10.3 ) Pub Date : 2019-08-28 , DOI: 10.1186/s40425-019-0676-z
Wanfeng Gao ₁ , Xiaoyun Zhang ₁ , Wendong Yang ₁ , Daolei Dou ₂ , Heng Zhang ₁ , Yuanhao Tang ₁ , Weilong Zhong ₁ , Jing Meng ₁ , Yun Bai ₃ , Yanrong Liu ₄ , Lan Yang ₄ , Shuang Chen ₄ , Huijuan Liu _{1,

5} , Cheng Yang _{1,

4} , Tao Sun _{1,

4}

Affiliation

背景技术髓样抑制细胞（MDSC）是免疫抑制细胞，在免疫逃逸，PD-1 / PD-L1抑制剂耐受性和肿瘤进展中起重要作用。因此，MDSCs是癌症免疫治疗的潜在目标。在这项研究中，我们从中药库中筛选了一种有效的多形核MDSC（PMN-MDSC）抑制剂，并评估了其与PD-1抑制剂的协同抗肿瘤作用。方法在本研究中，我们发现PMN-MDSCs在黑色素瘤（B16-F10）荷瘤小鼠的脾脏和骨髓中大量积聚。然后，我们通过蛋白质组学和Cytoscape分析确定了荷瘤小鼠PMN-MDSCs上调KEGG通路中的前10个关键蛋白。然后通过分子对接和对接分数的权重计算，将关键蛋白质用作从中药库（20000种化合物）中筛选PMN-MDSC抑制剂的目标。最后，通过体外蛋白质组学和代谢组学分析以及体内黑色素瘤（B16-F10）和三阴性乳腺癌（4 T1）小鼠肿瘤模型验证了该抑制剂的抑制作用。结果中药复方saposhnikovia根提取物Prim-O-glucosylcimifugin（POG）可以与靶蛋白良好结合，并通过抑制精氨酸代谢和三羧酸循环（TCA循环）来抑制PMN-MDSCs的增殖，代谢和免疫抑制能力。POG还可以增加肿瘤中CD8 T淋巴细胞的浸润，并增强PD-1抑制剂在B16-F10和4种T1小鼠肿瘤模型中的抗肿瘤作用。结论POG已成功从中药库中筛选出PMN-MDSC抑制剂。POG与PD-1抑制剂具有良好的协同抗肿瘤作用。这项研究为增强PD-1抑制剂在临床应用中的功效提供了潜在的选择。

"点击查看英文标题和摘要"

Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells.

BACKGROUND Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that play an important role in immune evasion, PD-1/PD-L1 inhibitor tolerance and tumour progression. Therefore, MDSCs are potential targets for cancer immunotherapy. In this study, we screened an effective polymorphonuclear MDSC (PMN-MDSC) inhibitor from the Traditional Chinese Medicine Library and evaluated its synergistic antitumour effects with PD-1 inhibitor. METHODS In the present study, we found that PMN-MDSCs accumulate heavily in the spleen and bone marrow of melanoma (B16-F10) tumour-bearing mice. Then, we determined the top 10 key proteins in the upregulated KEGG pathways of PMN-MDSCs in tumour-bearing mice through proteomics and Cytoscape analysis. The key proteins were then used as targets for the screening of PMN-MDSC inhibitors from the traditional Chinese Medicine Library (20000 compounds) through molecular docking and weight calculation of the docking score. Finally, the inhibitory effect of the inhibitor was verified through proteomics and metabolomics analysis in vitro and melanoma (B16-F10) and triple-negative breast cancer (4 T1) mouse tumour models in vivo. RESULTS Traditional Chinese medicine saposhnikovia root extract Prim-O-glucosylcimifugin (POG) could bind well to the target proteins and inhibit the proliferation, metabolism and immunosuppressive ability of PMN-MDSCs by inhibiting arginine metabolism and the tricarboxylic acid cycle (TCA cycle). POG could also increase CD8 T-lymphocyte infiltration in the tumours and enhance the antitumour effect of PD-1 inhibitor in B16-F10 and 4 T1 mouse tumour models. CONCLUSIONS POG was successfully screened from the traditional Chinese Medicine library as a PMN-MDSC inhibitor. POG exhibited a good synergistic antitumour effect with PD-1 inhibitor. This study provided a potential option for enhancing the efficacy of PD-1 inhibitors in clinical applications.

更新日期：2019-11-01

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