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Cancer Immunology, Immunotherapy

Published in:

01-08-2015 | Original Article

CD163+CD14+ macrophages, a potential immune biomarker for malignant pleural effusion

Authors: Fei Wang, Li Yang, Qun Gao, Lan Huang, Liping Wang, Jing Wang, Shengdian Wang, Bin Zhang, Yi Zhang

Published in: Cancer Immunology, Immunotherapy | Issue 8/2015

Abstract

Background

Malignant pleural effusion (MPE) is a common complication caused by malignant diseases. However, subjectivity, poor sensitivity, and substantial false-negative rates of cytology assay hamper accurate MPE diagnosis. The aim of this study was to assess whether CD163+CD14+ tumor-associated macrophages (TAMs) could be used as a biomarker for enabling sensitive and specific MPE diagnosis.

Methods

Pleural effusion samples and peripheral blood samples were collected from 50 MPE patients and 50 non-malignant pleural effusion (NMPE) patients, respectively. Flow cytometry was performed to analyze cell phenotypes, and RT-qPCR was used to detect cytokine expression in these monocytes and macrophages. A blinded validation study (n = 40) was subsequently performed to confirm the significance of CD163+CD14+ TAMs in MPE diagnosis. Student’s t test, rank sum test, and receiver operating characteristic curve analysis were used for statistical analysis.

Results

Notably, CD163+CD14+ cell frequency in MPE was remarkably higher than that in NMPE (P < 0.001). In a blinded validation study, a sensitivity of 78.9 % and a specificity of 100 % were obtained with CD163+CD14+ TAMs as a MPE biomarker. In total (n = 140), by using a cutoff level of 3.65 %, CD163+CD14+ cells had a sensitivity of 81.2 % and a specificity of 100 % for MPE diagnosis. Notably, MPE diagnosis by estimating CD163+CD14+ cells in pleural effusion could be obtained one week earlier than that obtained by cytological examination.

Conclusions

CD163+CD14+ macrophages could be potentially used as an immune diagnostic marker for MPE and has better assay sensitivity than that of cytological analysis.

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Heffner JE, Klein JS (2008) Recent advances in the diagnosis and management of malignant pleural effusions. Mayo Clin Proc 83:235–250. doi:10.4065/83.2.235 PubMedCrossRef

Stathopoulos GT (2011) Translational advances in pleural malignancies. Respirology 16:53–63. doi:10.1111/j.1440-1843.2010.01890.x PubMedCrossRef

Mishra EK, Davies RJ (2010) Advances in the investigation and treatment of pleural effusions. Expert Rev Respir Med 4:123–133PubMedCrossRef

Morgensztern D, Waqar S, Subramanian J, Trinkaus K, Govindan R (2012) Prognostic impact of malignant pleural effusion at presentation in patients with metastatic non-small-cell lung cancer. J Thorac Oncol 7:1485–1489. doi:10.1097/JTO.0b013e318267223a PubMedCrossRef

Salah S, Tanvetyanon T, Abbasi S (2012) Metastatectomy for extra-cranial extra-adrenal non-small cell lung cancer solitary metastases: systematic review and analysis of reported cases. Lung Cancer 75:9–14. doi:10.1016/j.lungcan.2011.07.014 PubMedCrossRef

Rakha EA, Patil S, Abdulla K, Abdulkader M, Chaudry Z, Soomro IN (2010) The sensitivity of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma. Diagn Cytopathol 38:874–879. doi:10.1002/dc.21303 PubMedCrossRef

Rodriguez-Panadero F, Romero-Romero B (2013) Current and future options for the diagnosis of malignant pleural effusion. Expert Opin Med Diagn 7:275–287. doi:10.1517/17530059.2013.786038 PubMedCrossRef

Basak SK, Veena MS, Oh S, Huang G, Srivatsan E, Huang M, Sharma S, Batra RK (2009) The malignant pleural effusion as a model to investigate intratumoral heterogeneity in lung cancer. PLoS ONE 4:e5884. doi:10.1371/journal.pone.0005884 PubMedCentralPubMedCrossRef

Stathopoulos GT, Kalomenidis I (2012) Malignant pleural effusion: tumor-host interactions unleashed. Am J Respir Crit Care Med 186:487–492. doi:10.1164/rccm.201203-0465PP PubMedCrossRef

10.

Ruffell B, Affara NI, Coussens LM (2012) Differential macrophage programming in the tumor microenvironment. Trends Immunol 33:119–126. doi:10.1016/j.it.2011.12.001 PubMedCentralPubMedCrossRef

11.

Coffelt SB, Hughes R, Lewis CE (2009) Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta 1796:11–18. doi:10.1016/j.bbcan.2009.02.004 PubMed

12.

Rogers TL, Holen I (2011) Tumour macrophages as potential targets of bisphosphonates. J Transl Med 9:177. doi:10.1186/1479-5876-9-177 PubMedCentralPubMedCrossRef

13.

Edin S, Wikberg ML, Dahlin AM, Rutegard J, Oberg A, Oldenborg PA, Palmqvist R (2012) The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS ONE 7:e47045. doi:10.1371/journal.pone.0047045 PubMedCentralPubMedCrossRef

14.

Chen C, Zhu YB, Shen Y, Zhu YH, Zhang XG, Huang JA (2012) Increase of circulating B7-H4-expressing CD68+ macrophage correlated with clinical stage of lung carcinomas. J Immunother 35:354–358. doi:10.1097/CJI.0b013e31824212c4 PubMedCrossRef

15.

Komohara Y, Niino D, Saito Y, Ohnishi K, Horlad H, Ohshima K, Takeya M (2013) Clinical significance of CD163(+) tumor-associated macrophages in patients with adult T-cell leukemia/lymphoma. Cancer Sci 104:945–951. doi:10.1111/cas.12167 PubMedCrossRef

16.

Reinartz S, Schumann T, Finkernagel F, Wortmann A, Jansen JM, Meissner W, Krause M, Schworer AM, Wagner U, Muller-Brusselbach S, Muller R (2014) Mixed-polarization phenotype of ascites-associated macrophages in human ovarian carcinoma: correlation of CD163 expression, cytokine levels and early relapse. Int J Cancer 134:32–42. doi:10.1002/ijc.28335 PubMedCentralPubMedCrossRef

17.

de Vos van Steenwijk PJ, Ramwadhdoebe TH, Goedemans R, Doorduijn EM, van Ham JJ, Gorter A, van Hall T, Kuijjer ML, van Poelgeest MI, van der Burg SH, Jordanova ES (2013) Tumor-infiltrating CD14-positive myeloid cells and CD8-positive T-cells prolong survival in patients with cervical carcinoma. Int J Cancer 133:2884–2894. doi:10.1002/ijc.28309

18.

Barros MH, Hassan R, Niedobitek G (2012) Tumor-associated macrophages in pediatric classical Hodgkin lymphoma: association with Epstein–Barr virus, lymphocyte subsets, and prognostic impact. Clin Cancer Res 18:3762–3771. doi:10.1158/1078-0432.ccr-12-0129 PubMedCrossRef

19.

Obermajer N, Wong JL, Edwards RP, Chen K, Scott M, Khader S, Kolls JK, Odunsi K, Billiar TR, Kalinski P (2013) Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling. J Exp Med 210:1433–1445. doi:10.1084/jem.20121277 PubMedCentralPubMedCrossRef

20.

Pass HI, Levin SM, Harbut MR, Melamed J, Chiriboga L, Donington J, Huflejt M, Carbone M, Chia D, Goodglick L, Goodman GE, Thornquist MD, Liu G, de Perrot M, Tsao MS, Goparaju C (2012) Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma. N Engl J Med 367:1417–1427. doi:10.1056/NEJMoa1115050 PubMedCentralPubMedCrossRef

21.

Komohara Y, Jinushi M, Takeya M (2014) Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci 105:1–8. doi:10.1111/cas.12314 PubMedCrossRef

22.

Shirabe K, Mano Y, Muto J, Matono R, Motomura T, Toshima T, Takeishi K, Uchiyama H, Yoshizumi T, Taketomi A, Morita M, Tsujitani S, Sakaguchi Y, Maehara Y (2012) Role of tumor-associated macrophages in the progression of hepatocellular carcinoma. Surg Today 42:1–7. doi:10.1007/s00595-011-0058-8 PubMedCrossRef

23.

Pettersen JS, Fuentes-Duculan J, Suarez-Farinas M, Pierson KC, Pitts-Kiefer A, Fan L, Belkin DA, Wang CQ, Bhuvanendran S, Johnson-Huang LM, Bluth MJ, Krueger JG, Lowes MA, Carucci JA (2011) Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated. J Invest Dermatol 131:1322–1330. doi:10.103/jid.2011.9 PubMedCentralPubMedCrossRef

24.

Capece D, Fischietti M, Verzella D, Gaggiano A, Cicciarelli G, Tessitore A, Zazzeroni F, Alesse E (2013) The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int 2013:187204. doi:10.1155/2013/187204 PubMedCentralPubMedCrossRef

25.

Walter RB, Bachli EB, Schaer DJ, Ruegg R, Schoedon G (2003) Expression of the hemoglobin scavenger receptor (CD163/HbSR) as immunophenotypic marker of monocytic lineage in acute myeloid leukemia. Blood 101:3755–3756. doi:10.1182/blood-2002-11-3414 PubMedCrossRef

26.

Garcia C, Gardner D, Reichard KK (2008) CD163: a specific immunohistochemical marker for acute myeloid leukemia with monocytic differentiation. Appl Immunohistochem Mol Morphol 16:417–421. doi:10.1097/PAI.0b013e31815db477 PubMedCrossRef

27.

Lau SK, Chu PG, Weiss LM (2004) CD163: a specific marker of macrophages in paraffin-embedded tissue samples. Am J Clin Pathol 122:794–801. doi:10.1309/qhd6-yfn8-1kqx-uuh6 PubMedCrossRef

28.

Chung FT, Lee KY, Wang CW, Heh CC, Chan YF, Chen HW, Kuo CH, Feng PH, Lin TY, Wang CH, Chou CL, Chen HC, Lin SM, Kuo HP (2012) Tumor-associated macrophages correlate with response to epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small cell lung cancer. Int J Cancer 131:E227–E235. doi:10.1002/ijc.27403 PubMedCrossRef

29.

Ma J, Liu L, Che G, Yu N, Dai F, You Z (2010) The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC Cancer 10:112. doi:10.1186/1471-2407-10-112 PubMedCentralPubMedCrossRef

30.

Behnes CL, Bremmer F, Hemmerlein B, Strauss A, Strobel P, Radzun HJ (2014) Tumor-associated macrophages are involved in tumor progression in papillary renal cell carcinoma. Virchows Arch 464:191–196. doi:10.1007/s00428-013-1523-0 PubMedCrossRef

31.

Santoni M, Massari F, Amantini C, Nabissi M, Maines F, Burattini L, Berardi R, Santoni G, Montironi R, Tortora G, Cascinu S (2013) Emerging role of tumor-associated macrophages as therapeutic targets in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother 62:1757–1768. doi:10.1007/s00262-013-1487-6 PubMedCrossRef

32.

Helm O, Held-Feindt J, Grage-Griebenow E, Reiling N, Ungefroren H, Vogel I, Kruger U, Becker T, Ebsen M, Rocken C, Kabelitz D, Schafer H, Sebens S (2014) Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis. Int J Cancer 135:843–861. doi:10.1002/ijc.28736 PubMedCrossRef

33.

Lim MH, Garrettc J, Mowlem L, Yap E (2013) Diagnosing malignant pleural effusions: how do we compare? N Z Med J 126:42–48PubMed

34.

Gorgun D, Secik F, Midilli K, Akkaya V, Yildiz P (2013) Diagnostic and prognostic significance of survivin levels in malignant pleural effusion. Respir Med 107:1260–1265. doi:10.1016/j.rmed.2013.04.011 PubMedCrossRef

35.

Neumann V, Loseke S, Nowak D, Herth FJ, Tannapfel A (2013) Malignant pleural mesothelioma: incidence, etiology, diagnosis, treatment, and occupational health. Dtsch Arztebl Int 110:319–326. doi:10.3238/arztebl.2013.0319 PubMedCentralPubMed

36.

Rieux C, Boisdron-Celle M, Morel A, Fey L, Urban T, Hureaux J (2013) Biological diagnosis of resistance to erlotinib in a malignant pleural effusion. Rev Mal Respir 30:572–575. doi:10.1016/j.rmr.2013.02.010 PubMedCrossRef

37.

Johnston WW (1985) The malignant pleural effusion. A review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer 56:905–909PubMedCrossRef

38.

Sriram KB, Relan V, Clarke BE, Duhig EE, Windsor MN, Matar KS, Naidoo R, Passmore L, McCaul E, Courtney D, Yang IA, Bowman RV, Fong KM (2012) Pleural fluid cell-free DNA integrity index to identify cytologically negative malignant pleural effusions including mesotheliomas. BMC Cancer 12:428. doi:10.1186/1471-2407-12-428 PubMedCentralPubMedCrossRef

39.

Kaczmarek M, Sikora J (2012) Macrophages in malignant pleural effusions - alternatively activated tumor associated macrophages. Contemp Oncol (Pozn) 16:279–284. doi:10.5114/wo.2012.30054

40.

Mundt F, Heidari-Hamedani G, Nilsonne G, Metintas M, Hjerpe A, Dobra K (2014) Diagnostic and prognostic value of soluble syndecan-1 in pleural malignancies. Biomed Res Int 2014:419853. doi:10.1155/2014/419853 PubMedCentralPubMedCrossRef

41.

Xu C, Yu L, Zhan P, Zhang Y (2014) Elevated pleural effusion IL-17 is a diagnostic marker and outcome predictor in lung cancer patients. Eur J Med Res 19:23. doi:10.1186/2047-783x-19-23 PubMedCentralPubMedCrossRef

42.

Gong Y, Chen SX, Gao BA, Yao RC, Guan L (2014) Cell origins and significance of IL-17 in malignant pleural effusion. Clin Transl Oncol 16:807–813. doi:10.1007/s12094-013-1152-8 PubMedCrossRef

43.

Gonda K, Shibata M, Shimura T, Abe N, Suzuki S, Yasuda M, Nakamura I, Ohtake T, Ohki S, Watanabe T, Fujimori K, Ohto H, Takenoshita S (2012) Changes in myeloid-derived suppressor cells in malignant effusions of cancer patients following cancer chemotherapy. Gan To Kagaku Ryoho 39:2088–2091PubMed

44.

Romano A, Parrinello NL, Vetro C, Forte S, Chiarenza A, Figuera A, Motta G, Palumbo GA, Ippolito M, Consoli U, Raimondo FD (2015) Circulating myeloid-derived suppressor cells correlate with clinical outcome in Hodgkin lymphoma patients treated up-front with a risk-adapted strategy. Br J Haematol 168:689–700. doi:10.1111/bjh.13198 PubMedCrossRef

45.

Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, Robinson SC, Balkwill FR (2008) “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205:1261–1268. doi:10.1084/jem.20080108 PubMedCentralPubMedCrossRef

Title: CD163+CD14+ macrophages, a potential immune biomarker for malignant pleural effusion
Authors: Fei Wang
Li Yang
Qun Gao
Lan Huang
Liping Wang
Jing Wang
Shengdian Wang
Bin Zhang
Yi Zhang
Publication date: 01-08-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 8/2015
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-015-1701-9

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