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01-12-2016 | Original Article

Macrophage migration inhibitory factor (MIF) is induced by cytotoxic drugs and is involved in immune escape and migration in childhood rhabdomyosarcoma

Authors: Sarah Maria Johler, Jörg Fuchs, Guido Seitz, Sorin Armeanu-Ebinger

Published in: Cancer Immunology, Immunotherapy | Issue 12/2016

Abstract

Macrophage migration inhibitory factor (MIF) is known to be involved in oncogenic transformation, tumour progression, and immunosuppression and is overexpressed in many solid tumours, including paediatric rhabdomyosarcoma (RMS). We investigated the function of MIF in RMS during treatment with cytotoxic drugs. RMS cell lines were analysed by flow cytometry, immunofluorescence staining, and ELISA. We demonstrated the overexpression of MIF in RMS cells and the enhanced expression and secretion after treatment with cytotoxic agents. Migration assays of RMS cells revealed that inhibitors of MIF (ISO-1, Ant.III 4-IPP, Ant.V, sulforaphane (SF)) and blocking antibodies caused reduced migration, indicating a role for MIF in metastatic invasion. Additionally, we investigated the function of MIF in immune escape. The development of a population containing immunosuppressive myeloid-derived suppressor cells was promoted by incubation in conditioned medium of RMS cells comprising MIF and was reversed by MIF inhibitors but not by antibodies. Although most inhibitors may restore immune activity, Ant.III and 10 µM SF disturbed T cell proliferation in a CFSE assay, whereas T cell proliferation was not reduced by 3 µM SF, ISO-1 or antibodies. However, the inhibition of MIF by blocking antibodies did not increase the killing activity of allogenic PBMCs co-cultured with RMS cells. Our results reveal that MIF may be involved in an immune escape mechanism and demonstrate the involvement of MIF in immunogenic cell death during treatment with cytotoxic drugs. Targeting MIF may contribute to the restoration of immune sensitivity and the control of migration and metastatic invasion.

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Pastore G, Peris-Bonet R, Carli M, Martinez-Garcia C, Sanchez de Toledo J, Steliarova-Foucher E (2006) Childhood soft tissue sarcomas incidence and survival in European children (1978-1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer 42(13):2136–2149. doi:10.1016/j.ejca.2006.05.016 CrossRefPubMed

McDowell HP (2003) Update on childhood rhabdomyosarcoma. Arch Dis Child 88(4):354–357CrossRefPubMedPubMedCentral

Parham DM (2001) Pathologic classification of rhabdomyosarcomas and correlations with molecular studies. Mod Pathol 14(5):506–514. doi:10.1038/modpathol.3880339 CrossRefPubMed

Sun X, Guo W, Shen JK, Mankin HJ, Hornicek FJ, Duan Z (2015) Rhabdomyosarcoma: advances in molecular and cellular biology. Sarcoma 2015:232010. doi:10.1155/2015/232010 CrossRefPubMedPubMedCentral

Wachtel M, Runge T, Leuschner I, Stegmaier S, Koscielniak E, Treuner J, Odermatt B, Behnke S, Niggli FK, Schafer BW (2006) Subtype and prognostic classification of rhabdomyosarcoma by immunohistochemistry. J Clin Oncol 24(5):816–822. doi:10.1200/JCO.2005.03.4934 CrossRefPubMed

Pappo AS, Shapiro DN, Crist WM, Maurer HM (1995) Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 13(8):2123–2139PubMed

McCarthy N (2014) Rhabdomyosarcoma: flexibility could be important. Nat Rev Cancer 14(3):156–157. doi:10.1038/nrc3684 CrossRefPubMed

Huh WW, Skapek SX (2010) Childhood rhabdomyosarcoma: new insight on biology and treatment. Curr Oncol Rep 12(6):402–410. doi:10.1007/s11912-010-0130-3 CrossRefPubMed

Seitz G, Dantonello TM, Int-Veen C, Blumenstock G, Godzinski J, Klingebiel T, Schuck A, Leuschner I, Koscielniak E, Fuchs J, CWS-96 Study Group (2011) Treatment efficiency, outcome and surgical treatment problems in patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma: a report from the Cooperative Soft Tissue Sarcoma trial CWS-96. Pediatr Blood Cancer 56(5):718–724. doi:10.1002/pbc.22950 CrossRefPubMed

10.

Wolden SL, Anderson JR, Crist WM, Breneman JC, Wharam MD Jr, Wiener ES, Qualman SJ, Donaldson SS (1999) Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol 17(11):3468–3475PubMed

11.

Koscielniak E, Morgan M, Treuner J (2002) Soft tissue sarcoma in children: prognosis and management. Paediatr Drugs 4(1):21–28CrossRefPubMed

12.

Bhatia A, Kumar Y (2014) Cellular and molecular mechanisms in cancer immune escape: a comprehensive review. Expert Rev Clin Immunol 10(1):41–62. doi:10.1586/1744666X.2014.865519 CrossRefPubMed

13.

Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022. doi:10.1038/ni.2703 CrossRefPubMedPubMedCentral

14.

Armeanu-Ebinger S, Bonin M, Habig K, Poremba C, Koscielniak E, Godzinski J, Warmann SW, Fuchs J, Seitz G (2011) Differential expression of invasion promoting genes in childhood rhabdomyosarcoma. Int J Oncol 38(4):993–1000. doi:10.3892/ijo.2011.921 CrossRefPubMed

15.

Tarnowski M, Grymula K, Liu R, Tarnowska J, Drukala J, Ratajczak J, Mitchell RA, Ratajczak MZ, Kucia M (2010) Macrophage migration inhibitory factor is secreted by rhabdomyosarcoma cells, modulates tumor metastasis by binding to CXCR4 and CXCR7 receptors and inhibits recruitment of cancer-associated fibroblasts. Mol Cancer Res 8(10):1328–1343. doi:10.1158/1541-7786.MCR-10-0288 CrossRefPubMedPubMedCentral

16.

Repp AC, Mayhew ES, Apte S, Niederkorn JY (2000) Human uveal melanoma cells produce macrophage migration-inhibitory factor to prevent lysis by NK cells. J Immunol 165(2):710–715CrossRefPubMed

17.

Bach JP, Rinn B, Meyer B, Dodel R, Bacher M (2008) Role of MIF in inflammation and tumorigenesis. Oncology 75(3–4):127–133. doi:10.1159/000155223 CrossRefPubMed

18.

Shimizu T, Abe R, Nakamura H, Ohkawara A, Suzuki M, Nishihira J (1999) High expression of macrophage migration inhibitory factor in human melanoma cells and its role in tumor cell growth and angiogenesis. Biochem Biophys Res Commun 264(3):751–758. doi:10.1006/bbrc.1999.1584 CrossRefPubMed

19.

Rendon BE, Roger T, Teneng I, Zhao M, Al-Abed Y, Calandra T, Mitchell RA (2007) Regulation of human lung adenocarcinoma cell migration and invasion by macrophage migration inhibitory factor. J Biol Chem 282(41):29910–29918. doi:10.1074/jbc.M704898200 CrossRefPubMed

20.

Dessein AF, Stechly L, Jonckheere N, Dumont P, Monte D, Leteurtre E, Truant S, Pruvot FR, Figeac M, Hebbar M, Lecellier CH, Lesuffleur T, Dessein R, Grard G, Dejonghe MJ, de Launoit Y, Furuichi Y, Prevost G, Porchet N, Gespach C, Huet G (2010) Autocrine induction of invasive and metastatic phenotypes by the MIF-CXCR4 axis in drug-resistant human colon cancer cells. Cancer Res 70(11):4644–4654. doi:10.1158/0008-5472.CAN-09-3828 CrossRefPubMed

21.

Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13(5):587–596. doi:10.1038/nm1567 CrossRefPubMed

22.

Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R (2003) MIF signal transduction initiated by binding to CD74. J Exp Med 197(11):1467–1476. doi:10.1084/jem.20030286 CrossRefPubMedPubMedCentral

23.

Tarnowski M, Grymula K, Reca R, Jankowski K, Maksym R, Tarnowska J, Przybylski G, Barr FG, Kucia M, Ratajczak MZ (2010) Regulation of expression of stromal-derived factor-1 receptors: CXCR4 and CXCR7 in human rhabdomyosarcomas. Mol Cancer Res 8(1):1–14. doi:10.1158/1541-7786.MCR-09-0259 CrossRefPubMedPubMedCentral

24.

Choi S, Kim HR, Leng L, Kang I, Jorgensen WL, Cho CS, Bucala R, Kim WU (2012) Role of macrophage migration inhibitory factor in the regulatory T cell response of tumor-bearing mice. J Immunol 189(8):3905–3913. doi:10.4049/jimmunol.1102152 CrossRefPubMedPubMedCentral

25.

Simpson KD, Templeton DJ, Cross JV (2012) Macrophage migration inhibitory factor promotes tumor growth and metastasis by inducing myeloid-derived suppressor cells in the tumor microenvironment. J Immunol 189(12):5533–5540. doi:10.4049/jimmunol.1201161 CrossRefPubMedPubMedCentral

26.

Mittelbronn M, Platten M, Zeiner P, Dombrowski Y, Frank B, Zachskorn C, Harter PN, Weller M, Wischhusen J (2011) Macrophage migration inhibitory factor (MIF) expression in human malignant gliomas contributes to immune escape and tumour progression. Acta Neuropathol 122(3):353–365. doi:10.1007/s00401-011-0858-3 CrossRefPubMed

27.

Krockenberger M, Dombrowski Y, Weidler C, Ossadnik M, Honig A, Hausler S, Voigt H, Becker JC, Leng L, Steinle A, Weller M, Bucala R, Dietl J, Wischhusen J (2008) Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D. J Immunol 180(11):7338–7348CrossRefPubMedPubMedCentral

28.

Herrmann D, Seitz G, Fuchs J, Armeanu-Ebinger S (2012) Susceptibility of rhabdomyosarcoma cells to macrophage-mediated cytotoxicity. Oncoimmunology 1(3):279–286. doi:10.4161/onci.18612 CrossRefPubMedPubMedCentral

29.

Hinson AR, Jones R, Crose LE, Belyea BC, Barr FG, Linardic CM (2013) Human rhabdomyosarcoma cell lines for rhabdomyosarcoma research: utility and pitfalls. Front Oncol 3:183. doi:10.3389/fonc.2013.00183 CrossRefPubMedPubMedCentral

30.

Ellerkamp V, Lieber J, Nagel C, Wenz J, Warmann SW, Fuchs J, Armeanu-Ebinger S (2013) Pharmacological inhibition of beta-catenin in hepatoblastoma cells. Pediatr Surg Int 29(2):141–149. doi:10.1007/s00383-012-3237-9 CrossRefPubMed

31.

Armeanu-Ebinger S, Griessinger CM, Herrmann D, Fuchs J, Kneilling M, Pichler BJ, Seitz G (2014) PET/MR imaging and optical imaging of metastatic rhabdomyosarcoma in mice. J Nucl Med 55(9):1545–1551. doi:10.2967/jnumed.114.138578 CrossRefPubMed

32.

Lieber J, Dewerth A, Wenz J, Kirchner B, Eicher C, Warmann SW, Fuchs J, Armeanu-Ebinger S (2013) Increased efficacy of CDDP in a xenograft model of hepatoblastoma using the apoptosis sensitizer ABT-737. Oncol Rep 29(2):646–652. doi:10.3892/or.2012.2150 PubMed

33.

Lang P, Pfeiffer M, Muller I, Schumm M, Ebinger M, Koscielniak E, Feuchtinger T, Foll J, Martin D, Handgretinger R (2006) Haploidentical stem cell transplantation in patients with pediatric solid tumors: preliminary results of a pilot study and analysis of graft versus tumor effects. Klin Padiatr 218(6):321–326. doi:10.1055/s-2006-942256 CrossRefPubMed

34.

Mackall CL, Rhee EH, Read EJ, Khuu HM, Leitman SF, Bernstein D, Tesso M, Long LM, Grindler D, Merino M, Kopp W, Tsokos M, Berzofsky JA, Helman LJ (2008) A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin Cancer Res 14(15):4850–4858. doi:10.1158/1078-0432.CCR-07-4065 CrossRefPubMedPubMedCentral

35.

Meadors JL, Cui Y, Chen QR, Song YK, Khan J, Merlino G, Tsokos M, Orentas RJ, Mackall CL (2011) Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy. Pediatr Blood Cancer 57(6):921–929. doi:10.1002/pbc.23048 CrossRefPubMed

36.

Huang E, Rubin BP, Keller C (2011) The long road to immunotherapy for childhood rhabdomyosarcoma. Pediatr Blood Cancer 57(6):899–901. doi:10.1002/pbc.23136 CrossRefPubMed

37.

Hira E, Ono T, Dhar DK, El-Assal ON, Hishikawa Y, Yamanoi A, Nagasue N (2005) Overexpression of macrophage migration inhibitory factor induces angiogenesis and deteriorates prognosis after radical resection for hepatocellular carcinoma. Cancer 103(3):588–598. doi:10.1002/cncr.20818 CrossRefPubMed

38.

Legendre H, Decaestecker C, Nagy N, Hendlisz A, Schuring MP, Salmon I, Gabius HJ, Pector JC, Kiss R (2003) Prognostic values of galectin-3 and the macrophage migration inhibitory factor (MIF) in human colorectal cancers. Mod Pathol 16(5):491–504. doi:10.1097/01.MP.0000068235.45178.C1 CrossRefPubMed

39.

Meyer-Siegler KL, Bellino MA, Tannenbaum M (2002) Macrophage migration inhibitory factor evaluation compared with prostate specific antigen as a biomarker in patients with prostate carcinoma. Cancer 94(5):1449–1456CrossRefPubMed

40.

Alampour-Rajabi S, El Bounkari O, Rot A, Muller-Newen G, Bachelerie F, Gawaz M, Weber C, Schober A, Bernhagen J (2015) MIF interacts with CXCR7 to promote receptor internalization, ERK1/2 and ZAP-70 signaling, and lymphocyte chemotaxis. FASEB J 29(11):4497–4511. doi:10.1096/fj.15-273904 CrossRefPubMed

41.

Hudson JD, Shoaibi MA, Maestro R, Carnero A, Hannon GJ, Beach DH (1999) A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med 190(10):1375–1382CrossRefPubMedPubMedCentral

42.

Ren Y, Chan HM, Li Z, Lin C, Nicholls J, Chen CF, Lee PY, Lui V, Bacher M, Tam PK (2004) Upregulation of macrophage migration inhibitory factor contributes to induced N-Myc expression by the activation of ERK signaling pathway and increased expression of interleukin-8 and VEGF in neuroblastoma. Oncogene 23(23):4146–4154. doi:10.1038/sj.onc.1207490 CrossRefPubMed

43.

Telliez A, Furman C, Pommery N, Henichart JP (2006) Mechanisms leading to COX-2 expression and COX-2 induced tumorigenesis: topical therapeutic strategies targeting COX-2 expression and activity. Anticancer Agents Med Chem 6(3):187–208CrossRefPubMed

44.

Crichlow GV, Fan C, Keeler C, Hodsdon M, Lolis EJ (2012) Structural interactions dictate the kinetics of macrophage migration inhibitory factor inhibition by different cancer-preventive isothiocyanates. Biochemistry 51(38):7506–7514. doi:10.1021/bi3005494 CrossRefPubMedPubMedCentral

45.

Healy ZR, Liu H, Holtzclaw WD, Talalay P (2011) Inactivation of tautomerase activity of macrophage migration inhibitory factor by sulforaphane: a potential biomarker for anti-inflammatory intervention. Cancer Epidemiol Biomarkers Prev 20(7):1516–1523. doi:10.1158/1055-9965.EPI-11-0279 CrossRefPubMedPubMedCentral

46.

Merk M, Baugh J, Zierow S, Leng L, Pal U, Lee SJ, Ebert AD, Mizue Y, Trent JO, Mitchell R, Nickel W, Kavathas PB, Bernhagen J, Bucala R (2009) The Golgi-associated protein p115 mediates the secretion of macrophage migration inhibitory factor. J Immunol 182(11):6896–6906. doi:10.4049/jimmunol.0803710 CrossRefPubMedPubMedCentral

47.

Livni E, Halevy S, Stahl B, Joshua H (1987) The appearance of macrophage migration-inhibition factor in drug reactions. J Allergy Clin Immunol 80(6):843–849CrossRefPubMed

48.

Mattarollo SR, Loi S, Duret H, Ma Y, Zitvogel L, Smyth MJ (2011) Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res 71(14):4809–4820. doi:10.1158/0008-5472.CAN-11-0753 CrossRefPubMed

49.

Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, Schmitt E, Hamai A, Hervas-Stubbs S, Obeid M, Coutant F, Metivier D, Pichard E, Aucouturier P, Pierron G, Garrido C, Zitvogel L, Kroemer G (2005) Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med 202(12):1691–1701. doi:10.1084/jem.20050915 CrossRefPubMedPubMedCentral

50.

Vacchelli E, Aranda F, Eggermont A, Galon J, Sautes-Fridman C, Cremer I, Zitvogel L, Kroemer G, Galluzzi L (2014) Trial Watch: Chemotherapy with immunogenic cell death inducers. Oncoimmunology 3(1):e27878. doi:10.4161/onci.27878 CrossRefPubMedPubMedCentral

51.

Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G (2013) Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39(1):74–88. doi:10.1016/j.immuni.2013.06.014 CrossRefPubMed

52.

Simpson KD, Cross JV (2013) MIF: metastasis/MDSC-inducing factor? Oncoimmunology 2(3):e23337. doi:10.4161/onci.23337 CrossRefPubMedPubMedCentral

53.

Hussain F, Freissmuth M, Volkel D, Thiele M, Douillard P, Antoine G, Thurner P, Ehrlich H, Schwarz HP, Scheiflinger F, Kerschbaumer RJ (2013) Human anti-macrophage migration inhibitory factor antibodies inhibit growth of human prostate cancer cells in vitro and in vivo. Mol Cancer Ther 12(7):1223–1234. doi:10.1158/1535-7163.MCT-12-0988 CrossRefPubMed

Title: Macrophage migration inhibitory factor (MIF) is induced by cytotoxic drugs and is involved in immune escape and migration in childhood rhabdomyosarcoma
Authors: Sarah Maria Johler
Jörg Fuchs
Guido Seitz
Sorin Armeanu-Ebinger
Publication date: 01-12-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 12/2016
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-016-1896-4

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