Skip to main content

MAGEA4 expression in bone and soft tissue tumors: its utility as a target for immunotherapy and diagnostic marker combined with NY-ESO-1

Virchows Archiv volume 471, pages 383–392 (2017)Cite this article

Abstract

Cancer-testis (CT) antigens have promise as targets for immunotherapy, because of their restricted expression in tumor or testis tissue. MAGEA4 is both a MAGE family member and a CT antigen, and has attracted attention as a potential immunotherapeutic target. We investigated MAGEA4 expression by immunohistochemistry in bone and soft tissue tumor specimens that consisted of 35 malignant or intermediate and 24 benign histological subtypes, in order to evaluate its possible utility as an immunotherapy target and its potential use as a diagnostic marker when combined with another CT antigen, NY-ESO-1. Among these tumors, MAGEA4 was detected in 82.2% of synovial sarcomas, 67.7% of myxoid liposarcomas, 43.8% of osteosarcomas, 41.4% of angiosarcomas, 24.6% of malignant peripheral nerve sheath tumors (MPNSTs), and 21.4% of chondrosarcomas. NY-ESO-1 expression was found in 88.2% of myxoid liposarcomas, 61.1% of synovial sarcomas, 31.3% of osteosarcomas, 21.4% of pleomorphic liposarcomas, 16.7% of desmoplastic small round cell tumors, and 14.3% of chondrosarcomas. Benign tumors and non-tumorous tissue, except for testis tissue, did not express MAGEA4 or NY-ESO-1. Combined use of MAGEA4 and NY-ESO-1 increased the sensitivity, specificity, positive predictive values, and negative predictive values for distinguishing synovial sarcoma from spindle cell tumors and other mimicking tumors, compared to individual use of MAGEA4 or NY-ESO-1. Our results support the immunotherapy targeting MAGEA4 or NY-ESO-1 can be an ancillary therapy in the above-mentioned tumors, and the potential utility of MAGEA4 as an ancillary diagnostic marker for synovial sarcoma combined with NY-ESO-1.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Juretic A, Spagnoli GC, Schultz-Thater E, Sarcevic B (2003) Cancer/testis tumour-associated antigens: immunohistochemical detection with monoclonal antibodies. Lancet Oncol 4:104–109

    CAS  Article  PubMed  Google Scholar 

  2. Ikeda H, Lethé B, Lehmann F, van Baren JF, Baurain JF, de Smet C et al (1997) Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity 6:199–208

    CAS  Article  PubMed  Google Scholar 

  3. Duffour MT, Chaux P, Lurquin C, Cornelis GBT (1999) A MAGE-A4 peptide presented by HLA-A2 is recognized by cytolytic T lymphocytes. Eur J Immunol 29:3329–3337

    CAS  Article  PubMed  Google Scholar 

  4. Shafer J, Cruz C, Leen A, Ku S, Lu A, Rousseau A et al (2011) Antigen-specific cytotoxic T lymphocytes can target chemoresistant side-population tumor cells in Hodgkin lymphoma. Leuk Lymphoma 51:870–880

    Article  Google Scholar 

  5. Takahashi N, Ohkuri T, Homma S, Ohtake J, Wakita D, Togashi Y et al (2012) First clinical trial of cancer vaccine therapy with artificially synthesized helper/ killer-hybrid epitope long peptide of MAGE-A4 cancer antigen. Cancer Sci 103:150–153

    CAS  Article  PubMed  Google Scholar 

  6. Saito T, Wada H, Yamasaki M, Miyata H, Nishikawa H, Sato E et al (2014) High expression of MAGE-A4 and MHC class I antigens in tumor cells and induction of MAGE-A4 immune responses are prognostic markers of CHP-MAGE-A4 cancer vaccine. Vaccine 32:5901–5907

    CAS  Article  PubMed  Google Scholar 

  7. Kageyama S, Ikeda H, Miyahara Y, Imai N, Ishihara M, Saito K et al (2015) Adoptive transfer of MAGE-A4 T-cell receptor gene-transduced lymphocytes in patients with recurrent esophageal cancer. Clin Cancer Res 21:2268–2277

    CAS  Article  PubMed  Google Scholar 

  8. Resnick MB, Sabo E, Kondratev S, Kerner H, Spagnoli GC, Yakirevich E (2002) Cancer-testis antigen expression in uterine malignancies with an emphasis on carcinosarcomas and papillary serous carcinomas. Int J Cancer 101:190–195

    CAS  Article  PubMed  Google Scholar 

  9. Kocher T, Zheng M, Bolli M, Simon R, Forster T, Schultz-Thater E et al (2002) Prognostic relevance of MAGE-A4 tumor antigen expression in transitional cell carcinoma of the urinary bladder: a tissue microarray study. Int J Cancer 100:702–705

    CAS  Article  PubMed  Google Scholar 

  10. Sarcevic B, Spagnoli GC, Terracciano L, Schultz-Thater E, Heberer M, Gamulin M et al (2003) Expression of cancer/testis tumor associated antigens in cervical squamous cell carcinoma. Oncology 64:443–449

    CAS  Article  PubMed  Google Scholar 

  11. Bandić D, Juretić A, Sarcević B, Separovic V, Kujundzic-Tiljak M, Hudolin T et al (2006) Expression and possible prognostic role of MAGE-A4, NY-ESO-1, and HER-2 antigens in women with relapsing invasive ductal breast cancer: retrospective immunohistochemical study. Croat Med J 47:32–41

    PubMed  PubMed Central  Google Scholar 

  12. Montoro JR, Mamede RC, Neder Serafini L, Saggioro FP, Figueiredo DL, Silva WA Jr et al (2012) Expression of cancer-testis antigens MAGE-A4 and MAGE-C1 in oral squamous cell carcinoma. Head Neck 34:1123–1128

    Article  PubMed  Google Scholar 

  13. Jäger BE, Chen Y, Drijfhout JW, Karbach J, Ringhoffer M, Jager D et al (1998) Simultaneous humoral and cellular immune response against cancer–testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J Exp Med 187:265–270

    Article  PubMed  PubMed Central  Google Scholar 

  14. Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME et al (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29:917–924

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chen YT, Ross DS, Chiu R, Zhou XK, Chen YY, Lee P et al (2011) Multiple cancer/testis antigens are preferentially expressed in hormone-receptor negative and high-grade breast cancers. PLoS One 6:e17876. doi:10.1371/journal.pone.0017876

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Velazquez EF, Jungbluth AA, Yancovitz M, Gnjatic S, Adams S, Oneill D et al (2007) Expression of the cancer/testis antigen NY-ESO-1 in primary and metastatic malignant melanoma (MM)—correlation with prognostic factors. Cancer Immun 7:11

    PubMed  PubMed Central  Google Scholar 

  17. Kurashige T, Noguchi Y, Saika T, Ono T, Nagata Y, Jungbluth A et al (2001) NY-ESO-1 expression and immunogenicity associated with transitional cell carcinoma: correlation with tumor grade advances in brief NY-ESO-1 expression and immunogenicity associated with transitional cell carcinoma: correlation with tumor grade 1. Cancer Res 61:4671–4674

    CAS  PubMed  Google Scholar 

  18. Laban S, Atanackovic D, Luetkens T, Knecht R, Busch CJ, Freytag M et al (2014) Simultaneous cytoplasmic and nuclear protein expression of melanoma antigen-A family and NY-ESO-1 cancer-testis antigens represents an independent marker for poor survival in head and neck cancer. Int J Cancer 135:1142–1152

    CAS  Article  PubMed  Google Scholar 

  19. John T, Starmans MH, Chen YT, Russell PA, Barnett SA, White SC et al (2013) The role of cancer-testis antigens as predictive and prognostic markers in non-small cell lung cancer. PLoS One 8:e67876. doi:10.1371/journal.pone.0067876

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Iura K, Maekawa A, Kohashi K, Ishii T, Bekki H, Otsuka H et al (2016) Cancer-testis antigen expression in synovial sarcoma: NY-ESO-1, PRAME, MAGEA4 and MAGEA1. Hum pathol. doi:10.1016/j.humpath.2016.12.006

  21. Lai J-P, Robbins PF, Raffeld M, Aung PP, Tsokos M, Rosenberg SA et al (2012) NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis. Mod Pathol 25:854–858

    Article  PubMed  Google Scholar 

  22. Endo M, de Graaff MA, Ingram DR, Lim S, Lev DC, Briaire-de Bruijn IH et al (2014) NY-ESO-1 (CTAG1B) expression in mesenchymal tumors. Mod Pathol 28:587–595

    Article  PubMed  Google Scholar 

  23. Christopher DMF, Julia AB, Pancras CW, Hogendoorn FM (2013) WHO classification of tumor of oft tissue and bone, 4th edn. Int Agency Res Cancer, Lyon, pp 33–43

    Google Scholar 

  24. Cabezon T, Gromova I, Gromov P, Serizawa R, Timmermans Wielenga V, Kroman N et al (2012) Proteomic profiling of triple-negative breast carcinomas in combination with a three-tier orthogonal technology approach identifies Mage-A4 as potential therapeutic target in estrogen receptor negative breast cancer. Mol Cell Proteomics 12:381–394

    Article  PubMed  PubMed Central  Google Scholar 

  25. Iura K, Kohashi K, Hotokebuchi Y, Ishii T, Maekawa A, Yamada Y et al (2015) Cancer-testis antigens PRAME and NY-ESO-1 correlate with tumour grade and poor prognosis in myxoid liposarcoma. J Pathol Clin Res 1:144–159

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Italiano A, Cioffi A, Penel N, Levra MG, Delcambre C, Kalbacher E et al (2012) Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas. Cancer 118:3330–3336

    CAS  Article  PubMed  Google Scholar 

  27. Jacobs JF, Brasseur F, Hulsbergen-van de Kaa CA, van de Rakt MW, Figdor CG, Adema GJ et al (2007) Cancer-germline gene expression in pediatric solid tumors using quantitative real-time PCR. Int J Cancer 120:67–74

    CAS  Article  PubMed  Google Scholar 

  28. Zou C, Shen J, Tang Q, Yang Z, Yin J, Xie X et al (2012) Cancer-testis antigens expressed in osteosarcoma identified by gene microarray correlate with a poor patient prognosis. Cancer 118:1845–1855

    CAS  Article  PubMed  Google Scholar 

  29. Boring CC, Squires TS, Tong T (1993) Cancer statistics, 1993. CA Cancer J Clin 43:7–26

    CAS  Article  PubMed  Google Scholar 

  30. Lin C, Mak S, Meitner PA, Wolf JM, Bluman EM, Block JA et al (2002) Cancer/testis antigen CSAGE is concurrently expressed with MAGE in chondrosarcoma. Gene 285:269–278

    CAS  Article  PubMed  Google Scholar 

  31. Hruban RH, Shiu MH, Senie RT, Woodruff JM (1990) Malignant peripheral nerve sheath tumors of the buttock and lower extremity. Cancer 66:1253–1265

    CAS  Article  PubMed  Google Scholar 

  32. Nobeyama Y, Nakagawa H (2016) Aberrant demethylation and expression of MAGEB2 in a subset of malignant peripheral nerve sheath tumors from neurofibromatosis type 1. J Dermatol Sci 81:118–123

    CAS  Article  PubMed  Google Scholar 

  33. Dufresne A, Cassier P, Couraud L, Marec-Berard P, Meeus P, Alberti L et al (2012) Desmoplastic small round cell tumor: current management and recent findings. Sarcoma. doi:10.1155/2012/714986

Download references

Acknowledgments

We thank the Research Support Center, Graduate School of Medical Sciences, Kyushu University for the technical support. We also thank KN International for revising the English usage.

Author information

Affiliations

  1. Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan

    Kunio Iura, Kenichi Kohashi, Takeaki Ishii, Akira Maekawa, Hirofumi Bekki, Hiroshi Otsuka, Yuichi Yamada, Hidetaka Yamamoto & Yoshinao Oda

  2. Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Kunio Iura, Takeaki Ishii, Akira Maekawa, Hirofumi Bekki, Hiroshi Otsuka, Yoshihiro Matsumoto & Yukihide Iwamoto

Authors
  1. Kunio Iura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenichi Kohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takeaki Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akira Maekawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hirofumi Bekki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroshi Otsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuichi Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hidetaka Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoshihiro Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yukihide Iwamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yoshinao Oda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshinao Oda.

Ethics declarations

This study was approved the Ethics Committee of Kyushu University (No. 26-49) and conducted according to the principles embodied in the Declaration of Helsinki. Informed consent was obtained from the subjects or guardians.

Funding

This study was supported by a JSPS KAKEN Grant (No. 25293088) and by funds from the Scholarship Program of the Takeda Science Foundation.

Conflict of interest

The authors declare that they have no conflicts of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Iura, K., Kohashi, K., Ishii, T. et al. MAGEA4 expression in bone and soft tissue tumors: its utility as a target for immunotherapy and diagnostic marker combined with NY-ESO-1. Virchows Arch 471, 383–392 (2017). https://doi.org/10.1007/s00428-017-2206-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-017-2206-z

Keywords

  • MAGEA4
  • NY-ESO-1
  • Sarcoma
  • Immunotherapy
  • Cancer-testis antigen