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
"> Figure 1
<p>Differential macrophage response to different inflammatory cytokine stimuli. (<b>A</b>) Morphological and immunocytochemical images showing monocyte-derived macrophage (MDM) polarization to M1 or M2 functional phenotype using type 1 cytokine IFN−γ and lipopolysaccharide (LPS) or type 2 cytokine IL-4 and IL-13, respectively. (<b>B</b>) Increases in CD80+ M1 and CD206+ M2 MDMs were seen after treatment with IFN−γ /LPS or IL-4/IL-13, respectively, using flow-cytometry analysis. Green arrows point to the CD80+ M1 macrophage, while red arrows indicate CD206+ M2 macrophages. (<b>C</b>) Flow cytometry and morphology imaging of M1 and M2 cell sorting and isolation using the fluorescence-activated cell sorting (FACS) assay. (<b>D</b>) Compared with the H1299 cells treated with M1 conditioned medium, the H1299 cells cultured with M2 conditioned medium exhibited higher invasion ability at 18 h in matrigel study. APC: antigen-presenting cell.</p> "> Figure 2
<p><span class="html-italic">Astragalus polysaccharide</span> (PG2) enhances M1 polarization and down-regulates IL-4/IL-13-induced M2 polarization. Images from flow cytometric analyses showing (<b>A</b>) the differentiation of THP-1 monocyte into macrophages after 24 h incubation in phorbol 12-myristate 13-acetate (PMA), (<b>B</b>) incubation of MDM in IL-4 and IL-13 induced a CD206<sup>high</sup>CD80<sup>low</sup> M2 phenotype, while (<b>C</b>) incubation of MDM in PG2 16 mg/mL for 48 h induced a CD80<sup>high</sup>CD206<sup>low</sup> M1 phenotype. (<b>D</b>) A graphical representation of the differential effect of IL-4/IL-13 and low dose (8 mg/mL) or high dose (16 mg/mL) PG2 treatment on M1–M2 polarization. **<span class="html-italic">p</span> < 0.01</p> "> Figure 3
<p>The enhancement of M1 macrophage polarization by PG2 is akin to the effect of LPS/IFN-γ stimulation of MDMs. Images from flow cytometric analyses showing (<b>A</b>) the differentiation of THP-1 monocyte into macrophages after 24 h incubation in PMA; (<b>B</b>) MDMs after exposure to IFN-γ and LPS induced a CD80<sup>high</sup>CD206<sup>low</sup> M1 phenotype; (<b>C</b>) cancer cell culture medium (CCCM) induced 17.1% CD80+ and 61.9% CD206+ MDMs; (<b>D</b>) PG2-treatment of MDMs pre-incubated in CCCM induced a CD80<sup>high</sup>CD206<sup>low</sup> M1 phenotype, similar to IFN-γ/LPS exposure; (<b>E</b>) a graphical representation of the differential effect of IFN-γ/LPS, CCCM, and 16 mg/mL PG2 treatment on M1–M2 polarization. PG2 enhanced the M1 phenotype akin to IFN-γ/LPS exposure effect. **<span class="html-italic">p</span> < 0.01</p> "> Figure 4
<p>PG2 negatively modulates the secretion of tumor-promoting anti-inflammatory cytokines and inhibits the M2-MCM-induced cancer stem cell-like phenotype of NSCLC cells. (<b>A</b>) Western blot showing a dose-related up-regulation of CD80 and down-regulation of CD206 protein expressions in MDMs after PG2 treatment. (<b>B</b>) Representative histogram of ELISA result showing PG2 significantly inhibited IL-10-enhanced M2 macrophage proliferation and CCCM-cultivated M2 population, compared to the untreated control group. ELISA histogram showing that 16 mg/mL PG2 exposure significantly reversed the CCCM-enhanced (<b>C</b>) IL-10 and (<b>D</b>) IL-6 secretion by M2 cells. (<b>E</b>) Photo (<span class="html-italic">upper panel</span>) and graphical (<span class="html-italic">lower panel</span>) images showing that H441 and H1299 cells co-cultured with M1-MCM remained adherent, while M2-MCM co-cultured cells acquired an adhesion-independent cancer stem cell (CSC) phenotype. (<b>F</b>) PG2 inhibited the viability of tumorspheres grown from M2/H1299 co-culture in a dose-dependent manner. *<span class="html-italic">p</span> < 0.05, **<span class="html-italic">p</span> < 0.01, ***<span class="html-italic">p</span> < 0.001; β-actin served as loading control.</p> "> Figure 5
<p>PG2 suppresses tumorigenicity and metastasis in syngeneic C57BL/6 mice and potentiates cisplatin anticancer effect in vivo by modulating inflammation-associated macrophage activity and angiogenesis. (<b>A</b>) Photo images show the anticancer effect of cisplatin and/or PG2 in syngeneic C57BL/6 mice inoculated with 1.5 × 10<sup>3</sup> LLC1 cells. (<b>B</b>) Graphical representation of the effect of cisplatin and/or PG2 on the tumor size, tumor weight, and body weight in syngeneic C57BL/6 mice inoculated with LLC1 cells. (<b>C</b>) Photo images show the effect of cisplatin and/or PG2 on metastasis in syngeneic C57BL/6 mice inoculated with LLC1 cells. (<b>D</b>) Immunofluorescent staining showed that PG2 or cisplatin alone mildly reduced the expression of beta subunit (NF-κB), CD11b, and CD31, while combining cisplatin with PG2 significantly inhibited their expression in the tissue specimen. Red arrow, liver metastasis; ns, not significant; *<span class="html-italic">p</span> < 0.05, **<span class="html-italic">p</span> < 0.01, ***<span class="html-italic">p</span> < 0.001; DMSO, dimethyl sulfoxide</p> "> Figure 6
<p>PG2 modulated the CD80+ M1/CD206+ M2 macrophage population and increased the population of CD80+, CD103+, and CD86+ dendritic cells derived from peripheral blood mononuclear cells (PBMCs) of cancer patient’s ex vivo. The effect of PMA, LPS+INF-γ, or PG2 on the proportion of (<b>A</b>) CD80+ and (<b>B</b>) CD206+ cells, as shown by flow cytometry. Graphical representation of the effect of PG2 on the population of (<b>C</b>) CD80+, (<b>D</b>) CD103+, and (<b>E</b>) CD86+ dendritic cells derived from GM-CSF+IL-4-treated PBMCs of NSCLC patients. (<b>F</b>) Graphical representation of the effect of PG2 on the number of functional CD103+ dendritic cells derived from GM-CSF+IL-4-treated PBMCs of breast, colon, ovarian, or liver patients. 1: GM-CSF+IL4; 2: GM-CSF+IL4, followed by the treatment of PG2 (16 mg/mL); 3: GM-CSF+IL4, washed out, and followed by the treatment of PG2 (16 mg/mL); *<span class="html-italic">p</span> < 0.05, **<span class="html-italic">p</span> < 0.01.</p> "> Figure 7
<p>Graphical abstract. <span class="html-italic">Astragalus</span> polysaccharide (PG2) enhances the phenotypic polarization of macrophages, functional maturation of dendritic cells, and T cell-mediated immune responses for anticancer therapy. DCs: dendritic cells, GM-CSF: granulocyte-macrophage colony stimulating factor.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Reagents
2.2. Peripheral Blood Mononuclear Cells (PBMCs) Culture and Isolation of Dendritic Cells
2.3. Cell Lines and Culture
2.4. Western Blot
2.5. Flow Cytometry Analyses
2.6. Methylthiazolyldiphenyl-Tetrazolium Bromide (MTT) Viability Assay
2.7. Cell Migration and Invasion Assays
2.8. Colony Formation Assay
2.9. Enzyme-Linked Immunosorbent Assay (ELISA)
2.10. Tumor Implantation and Growth in Syngeneic Mice Models
2.11. Ethics Approval and Consent to Participate
2.12. Statistical Analysis
3. Results
3.1. Macrophages Respond Differentially to Different Inflammatory Cytokine Stimuli
3.2. PG2 Enhances M1 Polarization While Down-Regulating IL-4/IL-13-Induced M2 Polarization Dose-Dependently
3.3. The Enhancement of M1 Macrophage Polarization by PG2 Is Akin to the Effect of LPS/IFN-γ Stimulation of MDMs
3.4. PG2 Represses the Tumor-Promoting Effects of Anti-Inflammatory Cytokines and Inhibits the NSCLC Stem Cell-Like Phenotypes Induced by M2-Conditioned Medium
3.5. PG2 Suppresses Tumorigenicity and Metastasis in Syngeneic C57BL/6 Mice, and Potentiates Anticancer Effect of Cisplatin In Vivo by Modulating Inflammation-Associated Macrophage Activity and Angiogenesis
3.6. PG2 Up-Modulates the CD80+ M1/CD206+ M2 Macrophage Ratio and Increases the Population of CD80+, CD103+, and CD86+ Functionally Matured Dendritic Cells Ex Vivo
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Availability of Data and Materials
Abbreviations
References
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Bamodu, O.A.; Kuo, K.-T.; Wang, C.-H.; Huang, W.-C.; Wu, A.T.H.; Tsai, J.-T.; Lee, K.-Y.; Yeh, C.-T.; Wang, L.-S. 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. Nutrients 2019, 11, 2264. https://doi.org/10.3390/nu11102264
Bamodu OA, Kuo K-T, Wang C-H, Huang W-C, Wu ATH, Tsai J-T, Lee K-Y, Yeh C-T, Wang L-S. 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. Nutrients. 2019; 11(10):2264. https://doi.org/10.3390/nu11102264
Chicago/Turabian StyleBamodu, Oluwaseun Adebayo, Kuang-Tai Kuo, Chun-Hua Wang, Wen-Chien Huang, Alexander T.H. Wu, Jo-Ting Tsai, Kang-Yun Lee, Chi-Tai Yeh, and Liang-Shun Wang. 2019. "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" Nutrients 11, no. 10: 2264. https://doi.org/10.3390/nu11102264