Astragalus polysaccharides (PG2) Enhances the M1 Polarization of Macrophages, Functional Maturation of Dendritic Cells, and T Cell-Mediated Anticancer Immune Responses in Patients with Lung Cancer

Abstract

Background: Recently, we demonstrated that Astragalus polysaccharide (PG2), the active ingredient in dried roots of astragalus membranaceus, ameliorates cancer symptom clusters and improves quality of life (QoL) in patients with metastatic disease by modulating inflammatory cascade against the background roles of inflammatory cells, including macrophages, dendritic cells (DCs), and cytotoxic T lymphocytes (CTLs) in tumor initiation, metastasis, and progression. Nevertheless, the role of PG2 in the modulation of anticancer immunogenicity and therapeutic response remains relatively underexplored and unclear. Purpose: The present study investigates how and to what extent PG2 modulates cellular and biochemical components of the inflammatory cascade and enhances anticancer immunity, as well as the therapeutic implication of these bio-events in patients with lung cancer. Methods and Results: Herein, we demonstrated that PG2 significantly increased the M1/M2 macrophage polarization ratio in non-small cell carcinoma (NSCLC) H441 and H1299 cells. This PG2-induced preferential pharmacologic up-regulation of tumoral M1 population in vitro positively correlated with the downregulation of tumor-promoting IL-6 and IL-10 expression in NSCLC cell-conditioned medium, with concomitant marked inhibition of cell proliferation, clonogenicity, and tumorsphere formation. Our ex vivo results, using clinical sample from our NSCLC cohort, demonstrated that PG2 also promoted the functional maturation of DCs with consequent enhancement of T cell-mediated anticancer immune responses. Consistent with the in vitro and ex vivo results, our in vivo studies showed that treatment with PG2 elicited significant time-dependent depletion of the tumor-associated M2 population, synergistically enhanced the anti-M2-based anticancer effect of cisplatin, and inhibited xenograft tumor growth in the NSCLC mice models. Moreover, in the presence of PG2, cisplatin-associated dyscrasia and weight-loss was markedly suppressed. Conclusion: These results do indicate a therapeutically-relevant role for PG2 in modulating the M1/M2 macrophage pool, facilitating DC maturation and synergistically enhancing the anticancer effect of conventional chemotherapeutic agent, cisplatin, thus laying the foundation for further exploration of the curative relevance of PG2 as surrogate immunotherapy and/or clinical feasibility of its use for maintenance therapy in patients with lung cancer.

A Review of the Pharmacological Action of Astragalus Polysaccharide

“…Following the treatment of H9c2 cells with different concentrations of APS, the result showed that APS protected these cells from LPS-induced inflammatory injury. This effect (Wang et al, 1989;Wang et al, 2013;Yang et al, 2014;Liu et al, 2017;Lv et al, 2017;Bamodu et al, 2019) In vitro…”

“…APS activates T cells by inducing the differentiation of DCs (Liu et al, 2011). A recent study found that APS is the first effective regulator of tumor M1/M2 macrophage polarization and an effective activator of DC maturation (Bamodu et al, 2019). APS activates the proliferation of B cells and macrophages and increases the production of cytokines.…”

ANXA1 as a Prognostic and Immune Microenvironmental Marker for Gliomas Based on Transcriptomic Analysis and Experimental Validation

“…Previous studies have shown that the stromal cells in the TME are conducive to the tumor growth and invasion, and have an anti-tumor immune effect ( Guo and Deng, 2018 ; Giraldo et al, 2019 ). Furthermore, immune cells, such as T cells and M1 and M2 macrophages, play a key role in the anti-tumor response ( Bamodu et al, 2019 ; Heymann et al, 2019 ). Several immunotherapies have been shown to be effective, including immune checkpoint inhibition and therapeutic antibody applications.…”

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

“…Several researches have shown that polysaccharides stimulate the release of TNF-α and NO in macrophages, and they contribute to the anti-tumor activity and immune regulation of tumor-bearing hosts. Moreover, they can also enhance the antibacterial activity of neutrophils and promote the cytotoxicity of NK cells (Li W. et al, 2019;Bamodu et al, 2019;Del Corno et al, 2020).…”

“…The astragalus polysaccharide (APS) is the main active component of A. membranaceus extract, and the combined treatment strategy used with other drugs (such as cancer chemotherapy and immunosuppressants drugs) has also been proved to obviously reduce the toxicity of these drugs and enhance the therapeutic effect (Li et al, 2020). Bamodu et al (2019) proved that astragalus polysaccharides can significantly increase the polarization rate of M1/M2 macrophages in non-small cell lung cancer (NSCLC) cell lines, regulate the M1/M2 macrophage pool (M1 macrophages produce pro-inflammatory factors and enhance the expression of MHC-II and costimulatory molecules), enhancing the body's immune response. Using the results in vitro of the clinical samples of the NSCLC cohort it was confirmed that APS can also promote the functional maturation of DCs, enhance the T cell-mediated anti-cancer immune response, and synergistically enhance the therapeutic effect of cisplatin, which proves that it is a substitute in the clinical feasibility of immunotherapy.…”