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Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells
Gao, Wanfeng1,2; Zhang, Xiaoyun1,2; Yang, Wendong1,2; Dou, Daolei6; Zhang, Heng1,2; Tang, Yuanhao1,2; Zhong, Weilong1,2; Meng, Jing1,2; Bai, Yun7; Liu, Yanrong4,5; Yang, Lan4,5; Chen, Shuang4,5; Liu, Huijuan1,2,3; Yang, Cheng1,2,4,5; Sun, Tao1,2,4,5
2019-08-28
Source PublicationJOURNAL FOR IMMUNOTHERAPY OF CANCER
ISSN2051-1426
Volume7Issue:1Pages:15
AbstractBackground 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.
KeywordPrim-O-glucosylcimifugin Myeloid-derived suppressor cells Proliferation Metabolism PD-1 inhibitor
DOI10.1186/s40425-019-0676-z
Language英语
Funding ProjectNational 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 Research AreaOncology ; Immunology
WOS SubjectOncology ; Immunology
WOS IDWOS:000483333400002
PublisherBMC
Citation statistics
Document Type期刊论文
Identifierhttp://ir.amss.ac.cn/handle/2S8OKBNM/35668
Collection中国科学院数学与系统科学研究院
Corresponding AuthorLiu, Huijuan; Yang, Cheng; Sun, Tao
Affiliation1.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
Recommended Citation
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.
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