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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 polymorphonu...

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Autores principales: Gao, Wanfeng, Zhang, Xiaoyun, Yang, Wendong, Dou, Daolei, Zhang, Heng, Tang, Yuanhao, Zhong, Weilong, Meng, Jing, Bai, Yun, Liu, Yanrong, Yang, Lan, Chen, Shuang, Liu, Huijuan, Yang, Cheng, Sun, Tao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714432/
https://www.ncbi.nlm.nih.gov/pubmed/31462297
http://dx.doi.org/10.1186/s40425-019-0676-z
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author Gao, Wanfeng
Zhang, Xiaoyun
Yang, Wendong
Dou, Daolei
Zhang, Heng
Tang, Yuanhao
Zhong, Weilong
Meng, Jing
Bai, Yun
Liu, Yanrong
Yang, Lan
Chen, Shuang
Liu, Huijuan
Yang, Cheng
Sun, Tao
author_facet Gao, Wanfeng
Zhang, Xiaoyun
Yang, Wendong
Dou, Daolei
Zhang, Heng
Tang, Yuanhao
Zhong, Weilong
Meng, Jing
Bai, Yun
Liu, Yanrong
Yang, Lan
Chen, Shuang
Liu, Huijuan
Yang, Cheng
Sun, Tao
author_sort Gao, Wanfeng
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-019-0676-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-67144322019-09-04 Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells Gao, Wanfeng Zhang, Xiaoyun Yang, Wendong Dou, Daolei Zhang, Heng Tang, Yuanhao Zhong, Weilong Meng, Jing Bai, Yun Liu, Yanrong Yang, Lan Chen, Shuang Liu, Huijuan Yang, Cheng Sun, Tao J Immunother Cancer Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-019-0676-z) contains supplementary material, which is available to authorized users. BioMed Central 2019-08-28 /pmc/articles/PMC6714432/ /pubmed/31462297 http://dx.doi.org/10.1186/s40425-019-0676-z Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Gao, Wanfeng
Zhang, Xiaoyun
Yang, Wendong
Dou, Daolei
Zhang, Heng
Tang, Yuanhao
Zhong, Weilong
Meng, Jing
Bai, Yun
Liu, Yanrong
Yang, Lan
Chen, Shuang
Liu, Huijuan
Yang, Cheng
Sun, Tao
Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells
title Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells
title_full Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells
title_fullStr Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells
title_full_unstemmed Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells
title_short Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells
title_sort prim-o-glucosylcimifugin enhances the antitumour effect of pd-1 inhibition by targeting myeloid-derived suppressor cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714432/
https://www.ncbi.nlm.nih.gov/pubmed/31462297
http://dx.doi.org/10.1186/s40425-019-0676-z
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