Prim-O-glucosylcimifugin Enhances The Anti-tumor Effect Of PD-1 Inhibition By Targeting MDSCs

Background: Myeloid derived suppressor cells(MDSCs),which are immunosuppressive cells,play an important role in the immune evasion,tolerance of PD-1/PD-L1 inhibitors,and the progression of tumors.A number of studies have shown that MDSCs inhibitors can inhibit tumor growth and increase the sensitivity of PD-1 inhibitors.The goal of this study was to screen out effective MDSCs inhibitor from the Traditional Chinese Medicine Library,and evaluate its synergistic anti-tumor effects with PD-1 inhibitors,providing a theoretical basis for further anti-tumor drug research.Methods: In this study,we analyzed the aggregation and activity of PMN-MDSCs in B16-F10 tumor-bearing mice compared with naive mice;then,using molecular docking and weight calculations to screen PMN-MDSCs inhibitor from the Traditional Chinese Medicine Library(20000 traditional Chinese medicines)by targeting the top 10 key proteins in the upregulated KEGG pathways of PMN-MDSCs in B16-F10 tumor-bearing mice,which was determined by proteomics and Cytoscape analysis;further,we verified its inhibitory effect and inhibition mechanism on PMN-MDSCs through proteomics,metabolomics,molecular experiments,multiple functional experiments and B16-F10 mouse tumor model;finally,we verify its synergistic anti-tumor effects with PD-1 inhibitors in in mice tumor models of melanoma(B16-F10)and triple-negative breast cancer(4T1).Results: In this study,we found that PMN-MDSCs heavily accumulated in the spleens and bone marrows of B16-F10 tumor-bearing mice with enhanced immunosuppressive effects;The up-regulated proteins of B16-F10 tumor bearing PMN-MDSCs are mainly enriched in cell proliferation and cellular metabolic pathway and traditional Chinese medicine saposhnikovia root extract Prim-O-glucosylcimifugin(POG)could bind well to the target proteins;POG could inhibit arginine metabolism and tricarboxylic acid cycle(TCA cycle)by inhibiting the expression of Arg-1 and i NOS,thereby inhibiting the proliferation,metabolism and immunosuppressive ability of PMN-MDSCs and improving the immunosuppressive microenvironment of B16-F10 tumor and inhibiting its growth;POG could also enhance the anti-tumour effect of PD-1 inhibitor in the B16-F10 and 4T1 mouse tumour models.Conclusions: We successfully screened POG from the Traditional Chinese Medicine Library as a PMN-MDSCs inhibitor.POG has a good synergistic anti-tumor effect with PD-1 inhibitor.This study provides a potential option for enhancing the efficacy of PD-1 inhibitors in clinic.