Study On The Main Active Ingredients Of Platycodon Grandiflorum Trigger Anti-tumor Mechanism Through Immune Regulation

In the tumor microenvironment(TME),the activation of programmed death-1(PD-1)-programmed death ligand-1(PD-L1)pathway is one of the main signals of immune escape and tumor deterioration.Monoclonal antibody blocking therapy slows down the progression of various malignancies and prolongs the survival of patients effectively.However,this treatment resulted in serious immune-related adverse events(ir AEs)owning to systemic immune activation.Therefore,it is necessary to find low side-effect drugs that inhibit the local PD-1/PD-L1 signaling pathway of TME.Here,we discovered that the Platycodon grandiflorum(PG)reduced the expression of PD-1 on the surface of CD8~+T cells to exert anti-tumor effects in NSCLC.First of all,combining systems pharmacology strategies and clinical data analysis,we found that PG has the potential to immunomodulate T cells and suppress tumors.Secondly,in vivo and in vitro experiments confirmed the anti-tumor effect of PG.Mechanistically,we found that PG increased the infiltration and killing activity of CD8~+T cells,which was related to the decrease of PD-1~+CD8~+T cells.Furthermore,we confirmed that PG regulated the expression of PD-1 on the surface of CD8~+T via reducing the secretion of VEGF-A regulated by the level of P-STAT3 in tumor cells.Additionally,we found that PG also positively impacted the biological processes downstream of STAT3:apoptosis,cycle and proliferation.Overall,we demonstrated that PG-mediated down-regulation of PD-1 on the surface of CD8~+T cells represents a promising strategy to locally enhance T cell responses and improve anti-tumor immunity.