Platycodon grandiflorum Triggers Antitumor Immunity by Restricting PD-1 Expression of CD8+ T Cells in Local Tumor Microenvironment

Abstract

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. Clinically, the application of monoclonal antibodies slows down the progression of various malignancies and prolongs the survival of patients effectively. However, these treatments result in serious immune-related adverse events (irAEs) owning to systemic immune activation. Therefore, to achieve long-term therapeutic effects and low side effects, it is necessary to find drugs inhibiting the local PD-1/PD-L1 signaling pathway of the TME. Here, we discovered that Platycodon grandiflorum (PG), a medicine and food homology herb, reduced the expression of PD-1 on the surface of CD8+ T cells to exert antitumor effects in non-small cell lung cancer (NSCLC). Firstly, by 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 have confirmed the antitumor effect of the combination of Platycodin D and Platycodin D3, which is preferred and representative of the compounds. Mechanistically, 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 cells via reducing the secretion of VEGF-A regulated by the level of P-STAT3 in tumor cells. Additionally, PG also positively impacted the biological processes downstream of STAT3. Overall, we demonstrated that PG-mediated downregulation of PD-1 on the surface of CD8+ T cells represents a promising strategy to locally enhance T-cell responses and improve antitumor immunity.

Potential Effects of Traditional Chinese Medicine in Anti-Aging and Aging-Related Diseases: Current Evidence and Perspectives

“…Platycodon grandiflorum (PG), a medicine and food homology herb, can improve antitumor immunity by downregulating PD-1 expression of CD8+ T cells in the TME. 75 …”

Nano-formulated delivery of active ingredients from traditional Chinese herbal medicines for cancer immunotherapy

“…The natural medicine Platycodon grandiflorum is widely used in the field of biomedicine with immunomodulation, anti-inflammatory, anti-tumor, expectorant and cough, hypoglycemic, and anti-obesity effects. Recent investigation indicated P. grandiflorum effectively restricted the expression of PD-1 on CTLs within the tumor microenvironment, locally increasing the T cells responses while avoiding over-activation of systemic immunity in an in vivo non-small cell lung cancer model 105 . Combining active ingredients of CHMs with chemical or biological agents is a promising strategy to assist cancer immunotherapy.…”

From immune checkpoints to therapies: understanding immune checkpoint regulation and the influence of natural products and traditional medicine on immune checkpoint and immunotherapy in lung cancer

“…discovered that PG could reduce STAT3 phosphorylation and downregulate VEGF-A secretion in tumor cells. VEGF-A-VEGFR axis can upregulate PD-1 expression on CD8+ T cells; thus, PG indirectly inhibits CD8+ T cells PD-1 by inhibiting tumor VEGF-A secretion ( 265 ).…”

“…Salvia miltiorrhiza Bunge (Danshen) extract cryptotanshinone, combined with anti-PD-L1 antibody, can make LLC-bearing mice tumor-free and increase CD45+ leukocytes, CD4+, and CD8+ T cells infiltration in tumors ( 292 , 298 ). Some natural products, such as Platycodon grandiflorum and Sophocarpine, have been reported to enhance the efficacy of anti-PD-L1 antibodies, suppressing tumor growth ( 248 , 265 ). Evodiamine has shown the ability to enhance the effectiveness of anti-PD-1 monoclonal antibodies (mAb), suppressing tumor growth and improving survival in LLC mice ( 194 ).…”