Interleukin-17 and Prostaglandin E2 Are Involved in Formation of an M2 Macrophage- Dominant Microenvironment in Lung Cancer Lunxu Liu, MD, PhD, Dongxia.

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Interleukin-17 and Prostaglandin E2 Are Involved in Formation of an M2 Macrophage- Dominant Microenvironment in Lung Cancer Lunxu Liu, MD, PhD, Dongxia Ge, MD, PhD, Lin Ma, MD, Jiandong Mei, MD, Sen Liu, MD, Qiuyang Zhang, PhD, Fuqiang Ren, MD, Hu Liao, MD, Qiang Pu, MD, Tao Wang, MD, Zongbing You, MD, PhD Journal of Thoracic Oncology Volume 7, Issue 7, Pages 1091-1100 (July 2012) DOI: 10.1097/JTO.0b013e3182542752 Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Tumor-associated macrophages expressed IL-17RC and IL-17RA. A, H&E staining of lung adenocarcinoma; open arrows, adenocarcinoma cells; arrows, macrophages with hemosiderin deposits; arrowheads, red blood cells. B, IHC of IL-17RC; open arrows, adenocarcinoma cells; arrows, macrophages. C, Double staining of IL-17RC (dark purple) and CD68 (red); open arrows, adenocarcinoma cells; arrows, macrophages; square boxes indicate macrophages in the tumor stroma and a circle indicates macrophages in the tumor islet. D, Double staining of CD68 (dark purple) and IL-17RA (red); open arrow, adenocarcinoma cells; arrows, macrophages; square boxes indicate macrophages in the tumor stroma and a circle indicates macrophages in the tumor islet. Original magnifications, 200× for photomicrographs and 400× for inserts. E–G, Kaplan–Meier survival curves demonstrate the number or ratio of macrophages in correlation to patient's survival. Macrophage number represents an average number of IL-17RC/CD68 double stained cells in five high-power fields of each tumor specimen; a total of 48 specimens were separated into two groups by the median value, with one group having macrophage number or the ratio > median value and another group having macrophage number or the ratio < median value; statistical significance was analyzed using the log-rank test. The median number of macrophages was 23.4/mm2 in the tumor islets and 25.7/mm2 in the tumor stroma. The median ratio of macrophage number in the tumor islets divided by macrophage number in the tumor stroma was 0.9. IL-17RC, interleukin-17 receptor C; IL-17RA, interleukin-17 receptor A; H&E, hematoxylin and eosin; IHC, immunohistochemical. Journal of Thoracic Oncology 2012 7, 1091-1100DOI: (10.1097/JTO.0b013e3182542752) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Lung tumors recruited macrophages through expressing high levels of IL-17. A, IL-17 levels in 20 lung tumors and matched normal lung tissues. B, Migration of RAW264.7 macrophages in Transwell assays; RAW264.7 macrophages were plated in the upper chamber and human tissues were placed in the lower chamber; results represent averages and SEs (error bars) from 12 pairs of tissue samples. C, Migration of RAW264.7 macrophages in Transwell assays; 5 μg/ml of mouse control IgG or anti-IL-17 neutralizing antibodies were added into the lower chamber 1 hr before plating RAW264.7 macrophages in the upper chamber; results were from five pairs of tissue samples. D, Migration of RAW264.7 macrophages in Transwell assays; recombinant mouse IL-17 was added in the lower chamber; results were from five independent experiments. E, Migration of mouse peritoneal macrophages in Transwell assays; IL-17 was added in the lower chamber; results were representatives of three independent experiments. IL-17, interleukin-17. Journal of Thoracic Oncology 2012 7, 1091-1100DOI: (10.1097/JTO.0b013e3182542752) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Lung cancer cells induced M2-macrophage differentiation. A–E, real-time polymerase chain reaction analysis of mRNA expression in RAW264.7 macrophages. A and B, RAW264.7 macrophages were treated without or with 50 ng/ml of IL-4, INF-γ, and/or IL-17 for 3 hrs. C and D, RAW264.7 macrophages were cocultured with A549 or LNCaP cells for 24 hrs. E, RAW264.7 macrophages were treated with the Dulbecco's Modified Eagle Medium, conditioned medium from A549 cells (conditioned medium [CM]), boiled medium, or boiled CM for 24 hrs. F, Western blot analysis of arginase I expression in RAW264.7 macrophages treated with medium, boiled medium, CM, or boiled CM. mRNA, messenger ribonucleic acid; IL-17, interleukin-17. Journal of Thoracic Oncology 2012 7, 1091-1100DOI: (10.1097/JTO.0b013e3182542752) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Lung tumors synthesized PGE2 to induce M2-macrophage differentiation. A, PGE2 concentrations in the conditioned media from lung cancer cell lines; 1 × 105 cells were cultured in 5 ml of serum-free Dulbecco's Modified Eagle Medium for 24 hrs, and PGE2 levels in the media were determined by ELISA. B, Real-time polymerase chain reaction analysis of mRNA expression in RAW264.7 macrophages treated without or with PGE2 for 3 hrs. C, PGE2 levels in 20 lung tumors and matched normal lung tissues were measured by ELISA. D, Western blot analysis of COX-2 expression in 20 lung tumors and matched normal lung tissues; β-actin was probed to normalize the amounts of loaded proteins; four representative pairs are shown; N, normal lung tissue; T, lung tumor. E, Relative COX-2 levels are shown as ratios of COX-2/β-actin calculated by imaging analysis of protein bands on Western blots. F, Schematic summary of macrophage recruitment and differentiation in lung cancer. TH-17 cells in lung tumors secrete IL-17 that recruits monocytes/macrophages into the tumor microenvironment; lung cancer cells express COX-2 and secrete PGE2; then, PGE2 and other cytokines (e.g., IL-4, IL-10, IL-13, and IL-21) induce monocytes/macrophages to differentiate into M2 macrophages that express IL-1ra, IL-10 and arginase I. Interferon-γ, lipopolysaccharides, granulocyte–monocyte colony-stimulating factor, and TNFα induce monocytes/macrophages to differentiate into M1 macrophages that express inducible nitric oxide synthase, IL-18 and TNFα. M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth and metastasis by secretion of growth factors, vascular endothelial growth factors and matrix metalloproteinases. In lung cancer, the signals that induce M2-macrophage differentiation are more powerful than the signals that induce M1-macrophage differentiation, resulting in more M2 macrophages than M1 macrophages in the lung tumor microenvironment. PGE2, prostaglandin E2; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction; mRNA, messenger ribonucleic acid; IL-17, interleukin-17; COX-2, cyclooxygenase-2; TNFα, tumor necrosis factor α; IL-1ra, interleukin-1 receptor antagonist. Journal of Thoracic Oncology 2012 7, 1091-1100DOI: (10.1097/JTO.0b013e3182542752) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions