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

doi:10.1186/s40425-019-0676-z

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	Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells
	Gao, Wanfeng 1,2; Zhang, Xiaoyun 1,2; Yang, Wendong 1,2; Dou, Daolei 6; Zhang, Heng 1,2; Tang, Yuanhao 1,2; Zhong, Weilong 1,2; Meng, Jing 1,2; Bai, Yun 7; Liu, Yanrong 4,5; Yang, Lan 4,5; Chen, Shuang 4,5; Liu, Huijuan 1,2,3; Yang, Cheng 1,2,4,5; Sun, Tao 1,2,4,5
	2019-08-28
发表期刊	JOURNAL FOR IMMUNOTHERAPY OF CANCER
ISSN	2051-1426
卷号	7 期号:1 页码:15
摘要	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.
关键词	Prim-O-glucosylcimifugin Myeloid-derived suppressor cells Proliferation Metabolism PD-1 inhibitor
DOI	10.1186/s40425-019-0676-z
语种	英语
资助项目	National Natural Science Funds of China[81572838] ; National Natural Science Funds of China[81872374] ; National Natural Science Funds of China[81703581] ; National Natural Science Funds of China[81871972] ; Tianjin Science and Technology Project[15PTGCCX00140] ; Tianjin Science and Technology Project[18PTSYJC00060] ; Chinese National Major Scientific and Technological Special Project for "Significant New Drugs Development"[2018ZX09736-005] ; Chinese National Major Scientific and Technological Special Project for "Significant New Drugs Development"[SQ2018ZX090201] ; National Key Research and Development Program of China[2018YFA0507203] ; Postdoctoral support scheme for innovative talents[BX20180150] ; Chinese Postdoctoral Science Foundation[2018 M640228] ; Fundamental Research Funds for the Central Universities, Nankai University
WOS研究方向	Oncology ; Immunology
WOS类目	Oncology ; Immunology
WOS记录号	WOS:000483333400002
出版者	BMC
引用统计
文献类型	期刊论文
条目标识符	http://ir.amss.ac.cn/handle/2S8OKBNM/35668
专题	中国科学院数学与系统科学研究院
通讯作者	Liu, Huijuan; Yang, Cheng; Sun, Tao
作者单位	1.Nankai Univ, State Key Lab Med Chem Biol, Haihe Educ Pk,38 Tongyan Rd, Tianjin 300353, Peoples R China 2.Nankai Univ, Coll Pharm, Haihe Educ Pk,38 Tongyan Rd, Tianjin 300353, Peoples R China 3.Nankai Univ, Coll Life Sci, Tianjin, Peoples R China 4.Tianjin Int Joint Acad Biomed, Tianjin Key Lab Early Druggabil Evaluat Innovat D, Tianjin, Peoples R China 5.Tianjin Int Joint Acad Biomed, Tianjin Key Lab Mol Drug Res, Tianjin, Peoples R China 6.Nankai Univ, State Key Lab Med Chem Biol, Dept Expt Facil, Tianjin, Peoples R China 7.Univ Chinese Acad Sci, Chinese Acad Sci, Sch Econ & Management, Acad Math & Syst Sci, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Gao, Wanfeng,Zhang, Xiaoyun,Yang, Wendong,et al. Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells[J]. JOURNAL FOR IMMUNOTHERAPY OF CANCER,2019,7(1):15.
APA	Gao, Wanfeng.,Zhang, Xiaoyun.,Yang, Wendong.,Dou, Daolei.,Zhang, Heng.,...&Sun, Tao.(2019).Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells.JOURNAL FOR IMMUNOTHERAPY OF CANCER,7(1),15.
MLA	Gao, Wanfeng,et al."Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells".JOURNAL FOR IMMUNOTHERAPY OF CANCER 7.1(2019):15.