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.
Highlights
Lung cancer is one of the most frequently diagnosed malignancies and the leading cause of cancer death worldwide, with an estimated 234,030 new cases diagnosed and 154,050 deaths in the United States alone in 2018 [1]
After differentiation of the phorbol 12-myristate 13-acetate (PMA)-exposed human THP-1 monocytes into macrophages (MDMs), and stimulation with IFN-γ/LPS or IL-4/IL-13 for macrophage polarization (Figure 1A), immunofluorescence staining and flow cytometry was used to confirm the functional phenotype of the resultant cells based on expression of established macrophage markers, CD80 and CD206 for M1- and M2- polarized macrophages, respectively
A significant increase from 0.813% to 62.3% in the CD80+ M1 population was noted after IFN-γ/LPS activation (Figure 1B, upper panel), while the IL-4/IL-13 stimulation induced an increase from 0.817% to 52.8% in the CD206+ M2 macrophages (Figure 1B, lower panel)
Summary
Lung cancer is one of the most frequently diagnosed malignancies and the leading cause of cancer death worldwide, with an estimated 234,030 new cases diagnosed and 154,050 deaths in the United States alone in 2018 [1]. Methods and Results: 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. 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, 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
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