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01-12-2021 | Human Papillomavirus | Research

Influence of Epstein–Barr virus and human papillomavirus infection on macrophage migration inhibitory factor and macrophage polarization in nasopharyngeal carcinoma

Authors: Guofei Feng, Yifei Xu, Ning Ma, Kaoru Midorikawa, Shinji Oikawa, Hatasu Kobayashi, Satoshi Nakamura, Hajime Ishinaga, Zhe Zhang, Guangwu Huang, Kazuhiko Takeuchi, Mariko Murata

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

To assess the effects of Epstein–Barr virus (EBV) and human papillomavirus (HPV) infection on the tumor microenvironment, we examined the relationship between viral infection status, macrophage migration inhibitory factor (MIF), and tumor-associated macrophages in nasopharyngeal carcinoma (NPC).

Methods

A tissue microarray containing 150 cores from 90 patients with NPC and six with chronic inflammation was used. EBV and HPV status were detected using in situ hybridization with commercial EBER1 and HPV16/18 probes. Immunofluorescence double staining of MIF, pan-macrophage marker CD68, M1 macrophage marker CD11c, and M2 macrophage marker CD163 were analyzed using the same tissue microarray. The levels of these markers between NPC and inflammation cases and between tumor nests and stroma were compared. Correlations among these markers were analyzed.

Results

We found EBER1(+) cases in 90% of NPC patients, including 10% EBV/HPV co-infection. M1 macrophages mainly infiltrated the tumor nest, while M2 macrophages infiltrated the tumor stroma. We found a significant positive correlation between EBER1 levels and MIF levels in tumor nests and a significant positive correlation between HPV16/18 and CD11c(+) cell levels in NPC tissues.

Conclusions

It is suggested that MIF is associated with EBV, and M1 macrophage infiltration is affected by HPV status in NPC.

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Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394(10192):64–80. https://doi.org/10.1016/S0140-6736(19)30956-0.CrossRefPubMed

Lee AWM, Ng WT, Chan JYW, Corry J, Makitie A, Mendenhall WM, et al. Management of locally recurrent nasopharyngeal carcinoma. Cancer Treat Rev. 2019;79:101890. https://doi.org/10.1016/j.ctrv.2019.101890.CrossRefPubMed

Chen YP, Lv JW, Mao YP, Li XM, Li JY, Wang YQ, et al. Unraveling tumour microenvironment heterogeneity in nasopharyngeal carcinoma identifies biologically distinct immune subtypes predicting prognosis and immunotherapy responses. Mol Cancer. 2021;20(1):14. https://doi.org/10.1186/s12943-020-01292-5.CrossRefPubMedPubMedCentral

Chua MLK, Wee JTS, Hui EP, Chan ATC. Nasopharyngeal carcinoma. Lancet. 2016;387(10022):1012–24. https://doi.org/10.1016/S0140-6736(15)00055-0.CrossRefPubMed

Tan GW, Visser L, Tan LP, van den Berg A, Diepstra A. The Microenvironment in Epstein-Barr Virus-Associated Malignancies. Pathogens. 2018;7(2):40.CrossRefPubMedCentral

Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z. Tumor-associated macrophages: an accomplice in solid tumor progression. J Biomed Sci. 2019;26(1):78. https://doi.org/10.1186/s12929-019-0568-z.CrossRefPubMedPubMedCentral

Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95. https://doi.org/10.1172/JCI59643.CrossRefPubMedPubMedCentral

Weber M, Wehrhan F, Baran C, Agaimy A, Buttner-Herold M, Ozturk H, et al. Malignant transformation of oral leukoplakia is associated with macrophage polarization. J Transl Med. 2020;18(1):11. https://doi.org/10.1186/s12967-019-02191-0.CrossRefPubMedPubMedCentral

Medrek C, Ponten F, Jirstrom K, Leandersson K. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 2012;12(1):306. https://doi.org/10.1186/1471-2407-12-306.CrossRefPubMedPubMedCentral

10.

Taubert H, Eckstein M, Epple E, Jung R, Weigelt K, Lieb V, et al. Immune Cell-Associated Protein Expression Helps to Predict Survival in Muscle-Invasive Urothelial Bladder Cancer Patients after Radical Cystectomy and Optional Adjuvant Chemotherapy. Cells. 2021;10(1):159.CrossRefPubMedPubMedCentral

11.

Cho KY, Miyoshi H, Kuroda S, Yasuda H, Kamiyama K, Nakagawara J, et al. The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery. J Stroke Cerebrovasc Dis. 2013;22(7):910–8. https://doi.org/10.1016/j.jstrokecerebrovasdis.2012.11.020.CrossRefPubMed

12.

Ambarus CA, Krausz S, van Eijk M, Hamann J, Radstake TR, Reedquist KA, et al. Systematic validation of specific phenotypic markers for in vitro polarized human macrophages. J Immunol Methods. 2012;375(1–2):196–206. https://doi.org/10.1016/j.jim.2011.10.013.CrossRefPubMed

13.

Kindt N, Journe F, Laurent G, Saussez S. Involvement of macrophage migration inhibitory factor in cancer and novel therapeutic targets. Oncol Lett. 2016;12(4):2247–53. https://doi.org/10.3892/ol.2016.4929.CrossRefPubMedPubMedCentral

14.

Lechien JR, Nassri A, Kindt N, Brown DN, Journe F, Saussez S. Role of macrophage migration inhibitory factor in head and neck cancer and novel therapeutic targets: a systematic review. Head Neck. 2017;39(12):2573–84. https://doi.org/10.1002/hed.24939.CrossRefPubMed

15.

Barbosa de Souza Rizzo M, Brasilino de Carvalho M, Kim EJ, Rendon BE, Noe JT, Darlene Wise A, Mitchell RA. Oral squamous carcinoma cells promote macrophage polarization in an MIF-dependent manner. QJM. 2018;111(11):769–78.

16.

Pei XJ, Wu TT, Li B, Tian XY, Li Z, Yang QX. Increased expression of macrophage migration inhibitory factor and DJ-1 contribute to cell invasion and metastasis of nasopharyngeal carcinoma. Int J Med Sci. 2014;11(1):106–15. https://doi.org/10.7150/ijms.7264.CrossRefPubMedPubMedCentral

17.

Deng Z, Uehara T, Maeda H, Hasegawa M, Matayoshi S, Kiyuna A, et al. Epstein-Barr virus and human papillomavirus infections and genotype distribution in head and neck cancers. PLoS One. 2014;9(11):e113702. https://doi.org/10.1371/journal.pone.0113702.CrossRefPubMedPubMedCentral

18.

Huang WB, Chan JYW, Liu DL. Human papillomavirus and World Health Organization type III nasopharyngeal carcinoma: multicenter study from an endemic area in southern China. Cancer. 2018;124(3):530–6. https://doi.org/10.1002/cncr.31031.CrossRefPubMed

19.

Stenmark MH, McHugh JB, Schipper M, Walline HM, Komarck C, Feng FY, et al. Nonendemic HPV-positive nasopharyngeal carcinoma: association with poor prognosis. Int J Radiat Oncol Biol Phys. 2014;88(3):580–8. https://doi.org/10.1016/j.ijrobp.2013.11.246.CrossRefPubMedPubMedCentral

20.

Kano M, Kondo S, Wakisaka N, Moriyama-Kita M, Nakanishi Y, Endo K, et al. The influence of human papillomavirus on nasopharyngeal carcinoma in Japan. Auris Nasus Larynx. 2017;44(3):327–32. https://doi.org/10.1016/j.anl.2016.07.015.CrossRefPubMed

21.

Svajdler M Jr, Kaspirkova J, Mezencev R, Laco J, Torday T, Dubinsky P, et al. Human papillomavirus and Epstein-Barr virus in nasopharyngeal carcinoma in a non-endemic eastern european population. Neoplasma. 2016;63(1):107–14. https://doi.org/10.4149/neo_2016_013.CrossRefPubMed

22.

Song X, Tao YG, Zeng L, Deng XY, Lee LM, Gong JP, et al. Latent membrane protein 1 encoded by Epstein-Barr virus modulates directly and synchronously cyclin D1 and p16 by newly forming a c-Jun/Jun B heterodimer in nasopharyngeal carcinoma cell line. Virus Res. 2005;113(2):89–99. https://doi.org/10.1016/j.virusres.2005.04.019.CrossRefPubMed

23.

Xiao W, Dong X, Zhao H, Han S, Nie R, Zhang X, et al. Expression of MIF and c-erbB-2 in endometrial cancer. Mol Med Rep. 2016;13(5):3828–34. https://doi.org/10.3892/mmr.2016.4992.CrossRefPubMedPubMedCentral

24.

Zhao YM, Wang L, Dai Z, Wang DD, Hei ZY, Zhang N, et al. Validity of plasma macrophage migration inhibitory factor for diagnosis and prognosis of hepatocellular carcinoma. Int J Cancer. 2011;129(10):2463–72. https://doi.org/10.1002/ijc.25918.CrossRefPubMed

25.

Olsson L, Lindmark G, Hammarstrom ML, Hammarstrom S, Sitohy B. Evaluating macrophage migration inhibitory factor 1 expression as a prognostic biomarker in colon cancer. Tumour Biol. 2020;42(6):1010428320924524. https://doi.org/10.1177/1010428320924524.CrossRefPubMed

26.

Tomiyasu M, Yoshino I, Suemitsu R, Okamoto T, Sugimachi K. Quantification of macrophage migration inhibitory factor mRNA expression in non-small cell lung cancer tissues and its clinical significance. Clin Cancer Res. 2002;8(12):3755–60.PubMed

27.

Liao B, Zhong BL, Li Z, Tian XY, Li Y, Li B. Macrophage migration inhibitory factor contributes angiogenesis by up-regulating IL-8 and correlates with poor prognosis of patients with primary nasopharyngeal carcinoma. J Surg Oncol. 2010;102(7):844–51. https://doi.org/10.1002/jso.21728.CrossRefPubMed

28.

Lee H, Rhee H, Kang HJ, Kim HS, Min BS, Kim NK, et al. Macrophage migration inhibitory factor may be used as an early diagnostic marker in colorectal carcinomas. Am J Clin Pathol. 2008;129(5):772–9. https://doi.org/10.1309/GFCLLRH8A68XKMJN.CrossRefPubMed

29.

MB DES, Curioni OA, Kanda JL, MB DEC. Serum and salivary macrophage migration inhibitory factor in patients with oral squamous cell carcinoma. Oncol Lett. 2014;8(5):2267–75. https://doi.org/10.3892/ol.2014.2513.CrossRef

30.

He XX, Yang J, Ding YW, Liu W, Shen QY, Xia HH. Increased epithelial and serum expression of macrophage migration inhibitory factor (MIF) in gastric cancer: potential role of MIF in gastric carcinogenesis. Gut. 2006;55(6):797–802. https://doi.org/10.1136/gut.2005.078113.CrossRefPubMedPubMedCentral

31.

Xue N, Xing S, Ma W, Sheng J, Huang Z, Xu Q. Combination of plasma MIF and VCA-IgA improves the diagnostic specificity for patients with nasopharyngeal carcinoma. Technol Cancer Res Treat. 2020;19:1533033820935773.PubMedPubMedCentral

32.

Noe JT, Mitchell RA. MIF-dependent control of tumor immunity. Front Immunol. 2020;11:609948. https://doi.org/10.3389/fimmu.2020.609948.CrossRefPubMedPubMedCentral

33.

Huang H, Liu X, Zhao F, Lu J, Zhang B, Peng X, et al. M2-polarized tumour-associated macrophages in stroma correlate with poor prognosis and Epstein-Barr viral infection in nasopharyngeal carcinoma. Acta Otolaryngol. 2017;137(8):888–94. https://doi.org/10.1080/00016489.2017.1296585.CrossRefPubMed

34.

Jackute J, Zemaitis M, Pranys D, Sitkauskiene B, Miliauskas S, Vaitkiene S, et al. Distribution of M1 and M2 macrophages in tumor islets and stroma in relation to prognosis of non-small cell lung cancer. BMC Immunol. 2018;19(1):3. https://doi.org/10.1186/s12865-018-0241-4.CrossRefPubMedPubMedCentral

35.

Mwafy SE, El-Guindy DM. Pathologic assessment of tumor-associated macrophages and their histologic localization in invasive breast carcinoma. J Egypt Natl Canc Inst. 2020;32(1):6. https://doi.org/10.1186/s43046-020-0018-8.CrossRefPubMed

36.

Chen YL. Prognostic significance of tumor-associated macrophages in patients with nasopharyngeal carcinoma: a meta-analysis. Medicine. 2020;99(39):e21999. https://doi.org/10.1097/MD.0000000000021999.CrossRefPubMedPubMedCentral

37.

Weber M, Buttner-Herold M, Hyckel P, Moebius P, Distel L, Ries J, et al. Small oral squamous cell carcinomas with nodal lymphogenic metastasis show increased infiltration of M2 polarized macrophages--an immunohistochemical analysis. J Craniomaxillofac Surg. 2014;42(7):1087–94. https://doi.org/10.1016/j.jcms.2014.01.035.CrossRefPubMed

38.

Ohri CM, Shikotra A, Green RH, Waller DA, Bradding P. Macrophages within NSCLC tumour islets are predominantly of a cytotoxic M1 phenotype associated with extended survival. Eur Respir J. 2009;33(1):118–26. https://doi.org/10.1183/09031936.00065708.CrossRefPubMed

39.

Ghoochani A, Schwarz MA, Yakubov E, Engelhorn T, Doerfler A, Buchfelder M, et al. MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis. Oncogene. 2016;35(48):6246–61. https://doi.org/10.1038/onc.2016.160.CrossRefPubMed

40.

Yaddanapudi K, Putty K, Rendon BE, Lamont GJ, Faughn JD, Satoskar A, et al. Control of tumor-associated macrophage alternative activation by macrophage migration inhibitory factor. J Immunol. 2013;190(6):2984–93. https://doi.org/10.4049/jimmunol.1201650.CrossRefPubMed

Title: Influence of Epstein–Barr virus and human papillomavirus infection on macrophage migration inhibitory factor and macrophage polarization in nasopharyngeal carcinoma
Authors: Guofei Feng
Yifei Xu
Ning Ma
Kaoru Midorikawa
Shinji Oikawa
Hatasu Kobayashi
Satoshi Nakamura
Hajime Ishinaga
Zhe Zhang
Guangwu Huang
Kazuhiko Takeuchi
Mariko Murata
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Human Papillomavirus
Epstein-Barr Virus
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08675-x

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Abstract

Background

Methods

Results

Conclusions

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