Antitumor Effect of Korean Red Ginseng through Blockade of PD-1/PD-L1 Interaction in a Humanized PD-L1 Knock-In MC38 Cancer Mouse Model

Abstract

Blocking immune checkpoints, programmed death-1 (PD-1) and its ligand PD-L1, has proven a promising anticancer strategy for enhancing cytotoxic T cell activity. Although we previously demonstrated that ginsenoside Rg3, Rh2, and compound K block the interaction of PD-1 and PD-L1, the antitumor effect through blockade of this interaction by Korean Red Ginseng alone is unknown. Therefore, we determined the effects of Korean Red Ginseng extract (RGE) on the PD-1/PD-L1 interaction and its antitumor effects using a humanized PD-1/PD-L1-expressing colorectal cancer (CRC) mouse model. RGE significantly blocked the interaction between human PD-1 and PD-L1 in a competitive ELISA. The CD8+ T cell-mediated tumor cell killing effect of RGE was evaluated using murine hPD-L1-expressing MC38 cells and tumor-infiltrating hPD-1-expressing CD8+ T cells isolated from hPD-L1 MC38 tumor-bearing hPD-1 mice. RGE also reduced the survival of hPD-L1 MC38 cells in a cell co-culture system using tumor-infiltrating CD8+ T cells as effector cells combined with hPD-L1 MC38 target cells. RGE or Keytruda (positive control) treatment markedly suppressed the growth of hPD-L1 MC38 allograft tumors, increased CD8+ T cell infiltration into tumors, and enhanced the production of Granzyme B. RGE exhibits anticancer effects through the PD-1/PD-L1 blockade, which warrants its further development as an immunotherapy.

Transformation of Ginsenosides by Lactiplantibacillus plantarum MB11 Fermentation: Minor Ginsenosides Conversion and Enhancement of Anti-Colorectal Cancer Activity

“…In addition, ginsenosides Rg3, CK, etc. can inhibit the proliferation of human colon cancer cells and thus exert anti-tumor effects [ 41 , 42 ]. This also lays the foundation for the subsequent clinical application of FTGs.…”

Ginsenosides: an immunomodulator for the treatment of colorectal cancer

“…Ginsenoside Rh2, Rg3, and CK block the interaction between PD-1 and its ligand PD-L1, enhancing the activity of cytotoxic T cells ( Yim et al, 2020 ). In the subcutaneous transplantation tumor model of MC38 in mice expressing humanized PD-1/PD-L1, red ginseng containing a large amount of ginsenoside Rh2, Rg3, and CK significantly inhibit tumor growth, increases the infiltration of CD8 + T cells into the tumor, and enhance the production of granzyme b ( Lee et al, 2023 ). Ginsenoside Rb1 and Rc reduce the number and size of intestinal adenomas in mouse models of intestinal adenomas.…”

Application of Traditional Chinese Medicine in Inhibiting the PD-1/PD-L1 Pathway in the Treatment of Gastric and Colon Cancers

“…Quel is widely used in Asian traditional medicine for its typical constituent polysaccharide peptide (PSP). PSPs are thought to have anticancer properties 85,86 and also have immunomodulatory properties. 87,88 Jian et al demonstrated that PSPs inhibited CRC proliferation by suppressing the expression of epidermal growth factor receptor and PD-L1.…”