The extracts of Astragalus membranaceus overcome tumor immune tolerance by inhibition of tumor programmed cell death protein ligand-1 expression

Abstract

A polysaccharide isolated from the radix of Astragalus membranaceus, called PG2, used in traditional Chinese medicine, with potential hematopoiesis inducing and immunomodulation activities. PG2 extracted from A. membranaceus has been demonstrated as a novel alternative medicine for cancer patients. Recently, we demonstrated that PG2 enhanced chemotherapy through bystander effect and reduced the expression of indoleamine 2, 3-dioxygenase 1 in tumor cells. Many tumors have been proven to have a high expression of programmed cell death protein ligand-1 (PD-L1), which binds with programmed cell death protein-1(PD-1) in immune cells, thus causing immune tolerance within the tumor microenvironment. With decreased expression of PD-L1, increased immune response can be observed, which might be helpful when developing tumor immunotherapy. The antitumor therapeutic effect mediated by PG2 may associate with an inflammatory immune response at the tumor site. However, the molecular mechanism that by which PG2 inhibits PD-L1 is still incompletely known. The expression of PD-L1 was decreased after tumor cells were treated with PG2. In addition, the cell signaling pathway in tumor cells was evaluated by Western blotting analysis after PG2 treatment. PG2 can downregulate the expression of PD-L1 on the cell surface via the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase beta-1 (p70S6K) pathway. In conclusion, our results indicate that PG2 inhibits PD-L1 expression and plays a crucial role in immunotherapy, which might be a promising strategy combined with other treatments.

Research Status and Molecular Mechanism of the Traditional Chinese Medicine and Antitumor Therapy Combined Strategy Based on Tumor Microenvironment

“…During in vitro and in vivo studies, apart from observing the effects on tumor cell proliferation, the related signaling pathways were explored, including the NF-kB and p38 MAPK signaling cascades mediated by TNFR1 in hepatocellular carcinoma cells (compound Kushen injection) (85) and the AKT pathway in gastric cancer and pancreatic cancer cells (Astragalus polysaccharide) (86,87). YIV-906, which is based on PHY906 (88), is a clinical observation drug that ensures >90% consistency in product quality (89). It is also the first Chinese medicinal project to be awarded a grant from the PO1 program of the National Cancer Center of the United States.…”

Natural Polysaccharides and Their Derivates: A Promising Natural Adjuvant for Tumor Immunotherapy

“…A study demonstrated that there was no significant difference in tumor inhibition compared with anti-PD-1 combined with ixabepilone or APS, indicating that APS can maintain an effective dose of anti-PD-1 antibody in vivo, and delay the progression of tumor or tumorigenesis by increasing the activity of T cells, which may improve the synergistic effect (Chang F.-L. et al, 2020). In addition, another research showed that APS enhances the chemotherapy by stimulating host immunity through reducing the PD-L1 expression of tumor surface (Chang H.-L. et al, 2020). It can reduce the expression of pro-inflammatory cytokines, promote the maturation of DCs and it also reduced the M2 macrophage population in patients with lung cancer (Huang et al, 2019).…”

The Synergism of Natural Compounds and Conventional Therapeutics against Colorectal Cancer Progression and Metastasis

“…Polysaccharides (PG2) are a mixture of Astragalus polysaccharides (APS) with diverse biological actions, including immunomodulatory, anticancer, and neuroprotective properties [103]. Chang et al [104] reported that PG2 isolated from Astragalus can inhibit the tumour cell production of indoleamine 2,3-dioxygenase 1 and PD-L1, through the Akt/mTOR/p70S6K pathway, thereby downregulating cell surface PD-L1 expression and enhances cisplatin sensitivity.…”