Archives of Dermatological Research

, Volume 296, Issue 7, pp 314–319 | Cite as

MAGE-A3 is a frequent tumor antigen of metastasized melanoma

  • Claudia Roeder
  • Beatrice Schuler-Thurner
  • Susanne Berchtold
  • Gisela Vieth
  • Peter von den Driesch
  • Gerold Schuler
  • Matthias Lüftl
Original Paper

Abstract

MAGE-3 or MAGE-A3 is one of the best-characterized tumor antigens. Due to its tumor-restricted expression pattern and its recognition by both cytotoxic and helper T cells it constitutes a promising tumor antigen for anticancer immunotherapy, notably of malignant melanoma. Surprisingly, however, only very limited information is available on the frequency and consistency of its expression in metastatic melanoma lesions. We have now investigated the presence of MAGE-A3 mRNA in 316 tumor samples from 147 melanoma patients by RT-PCR. MAGE-A3 mRNA was detectable in 62% of metastases, and expression did not depend on the site of the metastases (skin, lymph node, and internal organs), age, sex, or duration of disease. Southern blot hybridization of the PCR product enhanced sensitivity of detection, and 26% more samples (13/50 samples tested) scored positive, indicating an even higher MAGE-A3 mRNA frequency than determined by simple ethidium bromide gel analysis. In 62 patients, we were able to investigate MAGE-A3 expression in several metastases from the same patient, and unexpectedly, both MAGE-A3-positive and MAGE-A3-negative metastases were found in 32% of these patients (20 of 62). Immunohistochemistry (using mAb 57B) demonstrated that the expression pattern was usually also heterogeneous with positively and negatively stained tumor cells within one metastasis. However, most (90%) of the metastases (47/52) gave a partially positive signal. Taken together, MAGE-A3 is a common and frequent tumor antigen in metastasized melanoma, but its expression is often heterogeneous.

Keywords

Melanoma Immunotherapy CTA MAGE-A3 Tumor antigen 

References

  1. 1.
    Boon T, van der Bruggen P (1996) Human tumor antigens recognized by T lymphocytes. J Exp Med 183:725–729CrossRefPubMedGoogle Scholar
  2. 2.
    Brasseur F, Rimoldi D, Lienard D, Lethe B, Carrel S, Arienti F, Suter L, Vanwijck R, Bourlond A, Humblet Y (1995) Expression of MAGE genes in primary and metastatic cutaneous melanoma. Int J Cancer 63:375–380PubMedGoogle Scholar
  3. 3.
    Kirkin AF, Dzhandzhugazyan KN, Zeuthen J (2002) Cancer/testis antigens: structural and immunobiological properties. Cancer Invest 20:222–236CrossRefPubMedGoogle Scholar
  4. 4.
    Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen YT (2002) Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev 188:22–32CrossRefPubMedGoogle Scholar
  5. 5.
    Smith C, Cerundolo V (2001) Immunotherapy of melanoma. Immunology 104:1–7CrossRefPubMedGoogle Scholar
  6. 6.
    Zendman AJ, Ruiter DJ, van Muijen GN (2003) Cancer/testis-associated genes: identification, expression profile, and putative function. J Cell Physiol 194:272–288CrossRefPubMedGoogle Scholar
  7. 7.
    van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, van den Eynde B, Knuth A, Boon T (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254:1643–1647PubMedGoogle Scholar
  8. 8.
    van den Eynde B, Peeters O, De Backer O, Gaugler B, Lucas S, Boon T (1995) A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J Exp Med 182:689–698CrossRefPubMedGoogle Scholar
  9. 9.
    Gaugler B, van den Eynde B, van der Bruggen P, Romero P, Gaforio JJ, De Plaen E, Lethe B, Brasseur F, Boon T (1994) Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J Exp Med 179:921–930CrossRefPubMedGoogle Scholar
  10. 10.
    Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S, Taquet N, Rolland A, Taquet S, Coquery S, Wittkowski KM, Bhardwaj N, Pineiro L, Steinman R, Fay J (2001) Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res 61:6451–6458PubMedGoogle Scholar
  11. 11.
    Coulie PG, Karanikas V, Lurquin C, Colau D, Connerotte T, Hanagiri T, Van Pel A, Lucas S, Godelaine D, Lonchay C, Marchand M, van Baren N, Boon T (2002) Cytolytic T-cell responses of cancer patients vaccinated with a MAGE antigen. Immunol Rev 188:33–42CrossRefPubMedGoogle Scholar
  12. 12.
    Gajewski TF, Fallarino F, Ashikari A, Sherman M (2001) Immunization of HLA-A2+ melanoma patients with MAGE-3 or MelanA peptide-pulsed autologous peripheral blood mononuclear cells plus recombinant human interleukin 12. Clin Cancer Res 7:895s–901sPubMedGoogle Scholar
  13. 13.
    Hersey P, Menzies SW, Halliday GM, Nguyen T, Farrelly ML, DeSilva C, Lett M (2004) Phase I/II study of treatment with dendritic cell vaccines in patients with disseminated melanoma. Cancer Immunol Immunother 53:125–134CrossRefPubMedGoogle Scholar
  14. 14.
    Mackensen A, Herbst B, Chen JL, Kohler G, Noppen C, Herr W, Spagnoli GC, Cerundolo V, Lindemann A (2000) Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34(+) hematopoietic progenitor cells. Int J Cancer 86:385–392PubMedGoogle Scholar
  15. 15.
    Marchand M, Punt CJ, Aamdal S, Escudier B, Kruit WH, Keilholz U, Hakansson L, van Baren N, Humblet Y, Mulders P, Avril MF, Eggermont AM, Scheibenbogen C, Uiters J, Wanders J, Delire M, Boon T, Stoter G (2003) Immunisation of metastatic cancer patients with MAGE-3 protein combined with adjuvant SBAS-2: a clinical report. Eur J Cancer 39:70–77CrossRefPubMedGoogle Scholar
  16. 16.
    Marchand M, van Baren N, Weynants P, Brichard V, Dreno B, Tessier MH, Rankin E, Parmiani G, Arienti F, Humblet Y, Bourlond A, Vanwijck R, Lienard D, Beauduin M, Dietrich PY, Russo V, Kerger J, Masucci G, Jager E, De Greve J, Atzpodien J, Brasseur F, Coulie PG, van der Bruggen P, Boon T (1999) Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1. Int J Cancer 80:219–230CrossRefPubMedGoogle Scholar
  17. 17.
    Marchand M, Weynants P, Rankin E, Arienti F, Belli F, Parmiani G, Cascinelli N, Bourlond A, Vanwijck R, Humblet Y (1995) Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int J Cancer 63:883–885PubMedGoogle Scholar
  18. 18.
    Palucka AK, Dhodapkar MV, Paczesny S, Burkeholder S, Wittkowski KM, Steinman RM, Fay J, Banchereau J (2003) Single injection of CD34+ progenitor-derived dendritic cell vaccine can lead to induction of T-cell immunity in patients with stage IV melanoma. J Immunother 26:432–439CrossRefPubMedGoogle Scholar
  19. 19.
    Schuler-Thurner B, Schultz ES, Berger TG, Weinlich G, Ebner S, Woerl P, Bender A, Feuerstein B, Fritsch PO, Romani N, Schuler G (2002) Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J Exp Med 195:1279–1288CrossRefPubMedGoogle Scholar
  20. 20.
    Thurner B, Haendle I, Roder C, Dieckmann D, Keikavoussi P, Jonuleit H, Bender A, Maczek C, Schreiner D, von den DP, Brocker EB, Steinman RM, Enk A, Kampgen E, Schuler G (1999) Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 190:1669–1678CrossRefPubMedGoogle Scholar
  21. 21.
    Weber JS, Hua FL, Spears L, Marty V, Kuniyoshi C, Celis E (1999) A phase I trial of an HLA-A1 restricted MAGE-3 epitope peptide with incomplete Freund’s adjuvant in patients with resected high-risk melanoma. J Immunother 22:431–440PubMedGoogle Scholar
  22. 22.
    Jungbluth AA, Busam KJ, Kolb D, Iversen K, Coplan K, Chen YT, Spagnoli GC, Old LJ (2000) Expression of MAGE-antigens in normal tissues and cancer. Int J Cancer 85:460–465CrossRefPubMedGoogle Scholar
  23. 23.
    Hofbauer GF, Schaefer C, Noppen C, Boni R, Kamarashev J, Nestle FO, Spagnoli GC, Dummer R (1997) MAGE-3 immunoreactivity in formalin-fixed, paraffin-embedded primary and metastatic melanoma: frequency and distribution. Am J Pathol 151:1549–1553PubMedGoogle Scholar
  24. 24.
    Landry C, Brasseur F, Spagnoli GC, Marbaix E, Boon T, Coulie P, Godelaine D (2000) Monoclonal antibody 57B stains tumor tissues that express gene MAGE-A4. Int J Cancer 86:835–841CrossRefPubMedGoogle Scholar
  25. 25.
    Rimoldi D, Salvi S, Schultz-Thater E, Spagnoli GC, Cerottini JC (2000) Anti-MAGE-3 antibody 57B and anti-MAGE-1 antibody 6C1 can be used to study different proteins of the MAGE-A family. Int J Cancer 86:749–751PubMedGoogle Scholar
  26. 26.
    Kawakami Y, Rosenberg SA (1997) Human tumor antigens recognized by T-cells. Immunol Res 16:313–339PubMedGoogle Scholar
  27. 27.
    Nagorsen D, Scheibenbogen C, Marincola FM, Letsch A, Keilholz U (2003) Natural T cell immunity against cancer. Clin Cancer Res 9:4296–4303PubMedGoogle Scholar
  28. 28.
    Rufer N, Zippelius A, Batard P, Pittet MJ, Kurth I, Corthesy P, Cerottini JC, Leyvraz S, Roosnek E, Nabholz M, Romero P (2003) Ex vivo characterization of human CD8+ T subsets with distinct replicative history and partial effector functions. Blood 102:1779–1787CrossRefPubMedGoogle Scholar
  29. 29.
    Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D, Lejeune F, Rimoldi D, Guillaume P, Meidenbauer N, Mackensen A, Rufer N, Lubenow N, Speiser D, Cerottini JC, Romero P, Pittet MJ (2004) Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 64:2865–2873PubMedGoogle Scholar
  30. 30.
    Busam KJ, Iversen K, Berwick M, Spagnoli GC, Old LJ, Jungbluth AA (2000) Immunoreactivity with the anti-MAGE antibody 57B in malignant melanoma: frequency of expression and correlation with prognostic parameters. Mod Pathol 13:459–465CrossRefPubMedGoogle Scholar
  31. 31.
    Juretic A, Spagnoli GC, Schultz-Thater E, Sarcevic B (2003) Cancer/testis tumour-associated antigens: immunohistochemical detection with monoclonal antibodies. Lancet Oncol 4:104–109CrossRefPubMedGoogle Scholar
  32. 32.
    Dhodapkar MV, Osman K, Teruya-Feldstein J, Filippa D, Hedvat CV, Iversen K, Kolb D, Geller MD, Hassoun H, Kewalramani T, Coplan K, Comenzo RL, Chen YT, Jungbluth AA (2003) Expression of cancer/testis (CT) antigens MAGE-A1, MAGE-A3, MAGE-A4, CT-7, and NY-ESO-1 in malignant gammopathies is heterogeneous and correlates with site, stage and risk status of disease. Cancer Immun 3:9PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Claudia Roeder
    • 1
  • Beatrice Schuler-Thurner
    • 1
  • Susanne Berchtold
    • 1
  • Gisela Vieth
    • 1
  • Peter von den Driesch
    • 1
  • Gerold Schuler
    • 1
  • Matthias Lüftl
    • 1
  1. 1.Department of DermatologyUniversity Hospital of ErlangenErlangenGermany

Personalised recommendations