Cancer Immunology, Immunotherapy

, Volume 54, Issue 3, pp 219–228 | Cite as

Spontaneous T-cell responses against peptides derived from the Taxol resistance–associated gene-3 (TRAG-3) protein in cancer patients

  • Anders Meier
  • Sine Reker
  • Inge Marie Svane
  • Lars Holten-Andersen
  • Jürgen C. Becker
  • Ib Søndergaard
  • Mads Hald Andersen
  • Per thor Straten
Original Article

Abstract

Expression of the cancer-testis antigen Taxol resistance–associated gene-3 (TRAG-3) protein is associated with acquired paclitaxel (Taxol) resistance, and is expressed in various cancer types; e.g., breast cancer, leukemia, and melanoma. Thus, TRAG-3 represents an attractive target for immunotherapy of cancer. To identify HLA-A*02.01–restricted epitopes from TRAG-3, we screened cancer patients for spontaneous cytotoxic T-cell responses against TRAG-3–derived peptides. The TRAG-3 protein sequence was screened for 9mer and 10mer peptides possessing HLA-A*02.01–binding motifs. Of 12 potential binders, 9 peptides were indeed capable of binding to the HLA-A*02.01 molecule, with binding affinities ranging from strong to weak binders. Subsequently, lymphocytes from cancer patients (9 breast cancer patients, 12 melanoma patients, and 13 patients with hematopoietic malignancies) were analyzed for spontaneous reactivity against the panel of peptides by ELISpot assay. Spontaneous immune responses were detected against 8 epitope candidates in 7 of 9 breast cancer patients, 7 of 12 melanoma patients, and 5 of 13 patients with hematopoietic malignancies. In several cases, TRAG-3–specific CTL responses were scattered over several epitopes. Hence, no immunodominance of any single peptide was observed. Furthermore, single-peptide responses were detected in 2 of 12 healthy HLA-A2+ donors, but no responses were detectable in 9 HLA-A2 healthy donors or 4 HLA-A2 melanoma patients. The identified HLA-A*02.01–restricted TRAG-3–derived epitopes are targets for spontaneous immune responses in breast cancer, hematopoietic cancer, and melanoma patients. Hence, these epitopes represent potential target structures for future therapeutic vaccinations against cancer, possibly appropriate for strategies that combine vaccination and chemotherapy; i.e., paclitaxel treatment.

Keywords

Cancer-testis antigen Chemotherapy Peptide Tumor-associated antigen Tumor-specfic T cell 

References

  1. 1.
    Andersen MH, thor Straten P (2002) Survivin—a universal tumor antigen. Pathol Histopathol 17(2):669–675Google Scholar
  2. 2.
    Andersen MH, Tan L, Sondergaard I, Zeuthen J, Elliott T, Haurum JS (2000) Poor correspondence between predicted and experimental binding of peptides to class I MHC molecules. Tissue Antigens 55(6):519–531CrossRefPubMedGoogle Scholar
  3. 3.
    Andersen MH, Ostergaard Pedersen L, Becker JC, thor Straten P (2001) Identification of a cytotoxic T lymphocyte response to the apoptose inhibitor protein Survivin in cancer patients. Cancer Res 61:869–872PubMedGoogle Scholar
  4. 4.
    Anthony DD, Lehmann PV (2003) T-cell epitope mapping using the ELISPOT approach. Methods 29(3):260–269CrossRefPubMedGoogle Scholar
  5. 5.
    Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP (1998) Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 72:141–196PubMedGoogle Scholar
  6. 6.
    Bilsborough J, Panichelli C, Duffour MT, Warnier G, Lurquin C, Schultz ES, Thielemans K, Corthals J, Boon T, van Der BP (2002) A MAGE-3 peptide presented by HLA-B44 is also recognized by cytolytic T lymphocytes on HLA-B18. Tissue Antigens 60(1):16–24CrossRefPubMedGoogle Scholar
  7. 7.
    Brasseur F, Rimoldi D, Lienard D, Lethe B, Carrel S, Arienti F, Suter L, Vanwijck R, Bourlond A, Humblet Y et al (1995) Expression of MAGE genes in primary and metastatic cutaneous melanoma. Int J Cancer 63:375–380PubMedGoogle Scholar
  8. 8.
    Chen W, Masterman KA, Basta S, Mansour Haeryfar SM, Dimopoulos N, Knowles B, Bennink JR, Yewdell JW (2004) Cross-priming of CD8+ T cells by viral and tumor antigens is a robust phenomenon. Eur J Immunol 34(1):194–199Google Scholar
  9. 9.
    Chen Z, Zhu B, Wu Y (2002) Expression of TRAG-3 antigen in non-small-cell lung carcinomas. Lung Cancer 38(1):101–102CrossRefPubMedGoogle Scholar
  10. 10.
    Clark RE, Dodi IA, Hill SC, Lill JR, Aubert G, Macintyre AR, Rojas J, Bourdon A, Bonner PL, Wang L, Christmas SE, Travers PJ, Creaser CS, Rees RC, Madrigal JA (2001) Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein. Blood 98(10):2887–2893CrossRefPubMedGoogle Scholar
  11. 11.
    Coulie PG (2002) Cancer immunotherapy with MAGE antigens. Suppl Tumori 1(4):S63–S65PubMedGoogle Scholar
  12. 12.
    De Smet C, De Backer O, Faraoni I, Lurquin C, Brasseur F, Boon T (1996) The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc Natl Acad Sci U S A 93(14):7149–7153CrossRefPubMedGoogle Scholar
  13. 13.
    Dionne SO, Smith MH, Marincola FM, Lake DF (2003) Functional characterization of CTL against gp100 altered peptide ligands. Cancer Immunol Immunother 52(4):199–206PubMedGoogle Scholar
  14. 14.
    Duan Z, Feller AJ, Toh HC, Makastorsis T, Seiden MV (1999) TRAG-3, a novel gene, isolated from a taxol-resistant ovarian carcinoma cell line. Gene 229(1–2):75–81CrossRefPubMedGoogle Scholar
  15. 15.
    Duan Z, Duan Y, Lamendola DE, Yusuf RZ, Naeem R, Penson RT, Seiden MV (2003) Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicin-resistant human cancer cell lines. Clin Cancer Res 9(7):2778–2785PubMedGoogle Scholar
  16. 16.
    Feller AJ, Duan Z, Penson R, Toh HC, Seiden MV (2000) TRAG-3, a novel cancer/testis antigen, is overexpressed in the majority of melanoma cell lines and malignant melanoma. Anticancer Res 20(6B):4147–4151PubMedGoogle Scholar
  17. 17.
    Gabrilovich DI (2002) Dendritic cell vaccines for cancer treatment. Curr Opin Mol Ther 4(5):452–458PubMedGoogle Scholar
  18. 18.
    Godelaine D, Carrasco J, Lucas S, Karanikas V, Schuler-Thurner B, Coulie PG, Schuler G, Boon T, Van Pel A (2003) Polyclonal CTL responses observed in melanoma patients vaccinated with dendritic cells pulsed with a MAGE-3.A1 peptide. J Immunol 171(9):4893–4897PubMedGoogle Scholar
  19. 19.
    Gordan JD, Vonderheide RH (2002) Universal tumor antigens as targets for immunotherapy. Cytotherapy 4(4):317–327CrossRefPubMedGoogle Scholar
  20. 20.
    Gross DA, Graff-Dubois S, Opolon P, Cornet S, Alves P, Bennaceur-Griscelli A, Faure O, Guillaume P, Firat H, Chouaib S, Lemonnier FA, Davoust J, Miconnet I, Vonderheide RH, Kosmatopoulos K (2004) High vaccination efficiency of low-affinity epitopes in antitumor immunotherapy. J Clin Invest 113(3):425–433Google Scholar
  21. 21.
    Hudis C (2002) Adjuvant use of taxanes for patients with breast cancer: we see the tip of the iceberg. Clin Breast Cancer 3(5):326–332PubMedGoogle Scholar
  22. 22.
    Juretic A, Spagnoli GC, Schultz-Thater E, Sarcevic B (2003) Cancer/testis tumour-associated antigens: immunohistochemical detection with monoclonal antibodies. Lancet Oncol 4(2):104–109CrossRefPubMedGoogle Scholar
  23. 23.
    Karanikas V, Lurquin C, Colau D, van Baren N, De Smet C, Lethe B, Connerotte T, Corbiere V, Demoitie MA, Lienard D, Dreno B, Velu T, Boon T, Coulie PG (2003) Monoclonal anti-MAGE-3 CTL responses in melanoma patients displaying tumor regression after vaccination with a recombinant canarypox virus. J Immunol 171(9):4898–4904PubMedGoogle Scholar
  24. 24.
    Keogh E, Fikes J, Southwood S, Celis E, Chesnut R, Sette A (2001) Identification of new epitopes from four different tumor-associated antigens: recognition of naturally processed epitopes correlates with HLA-A*0201-binding affinity. J Immunol 167(2):787–796PubMedGoogle Scholar
  25. 25.
    Kerbel RS (2001) Molecular and physiologic mechanisms of drug resistance in cancer: an overview. Cancer Metastasis Rev 20(1–2):1–2CrossRefPubMedGoogle Scholar
  26. 26.
    Khayat D, Antoine EC, Coeffic D (2000) Taxol in the management of cancers of the breast and the ovary. Cancer Invest 18(3):242–260PubMedGoogle Scholar
  27. 27.
    Marchand M, Weynants P, Rankin E, Arienti F, Belli F, Parmiani G, Cascelli N, Bourlond A, Vanwijck R, Humblet Y, Canon JL, Laurent C, Naeyaert JM, Plangne R, Deraemaeker R, Knuth A, Jäger E, Brasseur F, Herman J, Coulie PG, Boon T (1995) Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int J Cancer 63:883–885PubMedGoogle Scholar
  28. 28.
    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(2):219–230CrossRefPubMedGoogle Scholar
  29. 29.
    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 (letter). Int J Cancer 63(6):883–885PubMedGoogle Scholar
  30. 30.
    Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D (1998) Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4(3):328–332PubMedGoogle Scholar
  31. 31.
    Parmiani G, Rivoltini L, Andreola G, Carrabba M (2000) Cytokines in cancer therapy. Immunol Lett 74(1):41–44CrossRefPubMedGoogle Scholar
  32. 32.
    Parmiani G, Castelli C, Dalerba P, Mortarini R, Rivoltini L, Marincola FM, Anichini A (2002) Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going? J Natl Cancer Inst 94(11):805–818Google Scholar
  33. 33.
    Pass HA, Schwarz SL, Wunderlich JR, Rosenberg SA (1998) Immunization of patients with melanoma peptide vaccines: immunologic assessment using the ELISPOT assay. Cancer J Sci Am 4(5):316–323PubMedGoogle Scholar
  34. 34.
    Rabinowich H, Banks M, Reichert TE, Logan TF, Kirkwood JM, Whiteside TL (1996) Expression and activity of signaling molecules in T lymphocytes obtained from patients with metastatic melanoma before and after interleukin 2 therapy. Clin Cancer Res 2(8):1263–1274PubMedGoogle Scholar
  35. 35.
    Rammensee HG, Weinschenk T, Gouttefangeas C, Stevanovi ES (2002) Towards patient-specific tumor antigen selection for vaccination. Immunol Rev 188(1):164–176CrossRefPubMedGoogle Scholar
  36. 36.
    Renkvist N, Castelli C, Robbins PF, Parmiani G (2001) A listing of human tumor antigens recognized by T cells. Cancer Immunol Immunother 50(1):3–15CrossRefPubMedGoogle Scholar
  37. 37.
    Reynolds SR, Zeleniuch-Jacquotte A, Shapiro RL, Roses DF, Harris MN, Johnston D, Bystryn JC (2003) Vaccine-induced CD8+ T-cell responses to MAGE-3 correlate with clinical outcome in patients with melanoma. Clin Cancer Res 9(2):657–662PubMedGoogle Scholar
  38. 38.
    Riley JP, Rosenberg SA, Parkhurst MR (2003) Stimulation of tumor-reactive T lymphocytes using mixtures of synthetic peptides derived from tumor-associated antigens with diverse MHC binding affinities. J Immunol Methods 276(1–2):103–119CrossRefPubMedGoogle Scholar
  39. 39.
    Romero P, Valmori D, Pittet MJ, Zippelius A, Rimoldi D, Levy F, Dutoit V, Ayyoub M, Rubio-Godoy V, Michielin O, Guillaume P, Batard P, Luescher IF, Lejeune F, Lienard D, Rufer N, Dietrich PY, Speiser DE, Cerottini JC (2002) Antigenicity and immunogenicity of Melan-A/MART-1 derived peptides as targets for tumor reactive CTL in human melanoma. Immunol Rev 188(1):81–96CrossRefPubMedGoogle Scholar
  40. 40.
    Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wunderlich JR, Parkhurst MR, Kawakami Y, Seipp CA, Einhorn JH, White DE (1998) Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4(3):321–327PubMedGoogle Scholar
  41. 41.
    Sangrajrang S, Fellous A (2000) Taxol resistance. Chemotherapy 46(5):327–334CrossRefPubMedGoogle Scholar
  42. 42.
    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(1):22–32CrossRefPubMedGoogle Scholar
  43. 43.
    Scanlan MJ, Simpson AJ, Old LJ (2004) The cancer/testis genes: review, standardization, and commentary. Cancer Immun 4:1PubMedGoogle Scholar
  44. 44.
    Schrama D, Andersen MH, Terheyden P, Schrøder L, Ostergaard Pedersen L, thor Straten P, Becker JC (2001) Oligoclonal TCR usage of melanocyte differentiation antigen-reactive T cells. Cancer Res 61:493–496PubMedGoogle Scholar
  45. 45.
    Schuler G, Schuler-Thurner B, Steinman RM (2003) The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 15(2):138–147CrossRefPubMedGoogle Scholar
  46. 46.
    Schultze JL, Vonderheide RH (2001) From cancer genomics to cancer immunotherapy: toward second-generation tumor antigens. Trends Immunol 22(9):516–523CrossRefPubMedGoogle Scholar
  47. 47.
    Simon GR, Bunn PA, Jr (2003) Taxanes in the treatment of advanced (stage III and IV) non-small cell lung cancer (NSCLC): recent developments. Cancer Invest 21(1):87–104CrossRefPubMedGoogle Scholar
  48. 48.
    Valmori D, Dutoit V, Lienard D, Rimoldi D, Pittet MJ, Champagne P, Ellefsen K, Sahin U, Speiser D, Lejeune F, Cerottini JC, Romero P (2000) Naturally occurring human lymphocyte antigen-A2 restricted CD8+ T-cell response to the cancer testis antigen NY-ESO-1 in melanoma patients. Cancer Res 60(16):4499–4506PubMedGoogle Scholar
  49. 49.
    Valmori D, Dutoit V, Rubio-Godoy V, Chambaz C, Lienard D, Guillaume P, Romero P, Cerottini JC, Rimoldi D (2001) Frequent cytolytic T-cell responses to peptide MAGE-A10(254–262) in melanoma. Cancer Res 61(2):509–512PubMedGoogle Scholar
  50. 50.
    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
  51. 51.
    van der Bruggen P, Zhang Y, Chaux P, Stroobant V, Panichelli C, Schultz ES, Chapiro J, Van den Eynde BJ, Brasseur F, Boon T (2002) Tumor-specific shared antigenic peptides recognized by human T cells. Immunol Rev 188(1):51–64CrossRefPubMedGoogle Scholar
  52. 52.
    Wolff AC (2001) Systemic therapy. Curr Opin Oncol 13(6):436–449CrossRefPubMedGoogle Scholar
  53. 53.
    Wu YZ, Zhao TT, Ni B, Zou LY, Liu HL, Zhu B (2003) Expression of TRAG-3 in breast cancer. Int J Cancer 107(1):167–168CrossRefPubMedGoogle Scholar
  54. 54.
    Yee C, Greenberg PD (2002) Modulating T-cell immunity to tumours: new strategies for monitoring T-cell responses. Nat Rev Cancer 2(6):409–419CrossRefPubMedGoogle Scholar
  55. 55.
    Zendman AJ, Ruiter DJ, van Muijen GN (2003) Cancer/testis-associated genes: identification, expression profile, and putative function. J Cell Physiol 194(3):272–288CrossRefPubMedGoogle Scholar
  56. 56.
    Zhu B, Chen Z, Cheng X, Lin Z, Guo J, Jia Z, Zou L, Wang Z, Hu Y, Wang D, Wu Y (2003) Identification of HLA-A*0201-restricted cytotoxic T lymphocyte epitope from TRAG-3 antigen. Clin Cancer Res 9(5):1850–1857PubMedGoogle Scholar
  57. 57.
    Zinkernagel RM (2002) On cross-priming of MHC class I-specific CTL: rule or exception? Eur J Immunol 32(9):2385–2392CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Anders Meier
    • 1
  • Sine Reker
    • 1
  • Inge Marie Svane
    • 2
  • Lars Holten-Andersen
    • 1
  • Jürgen C. Becker
    • 3
  • Ib Søndergaard
    • 4
  • Mads Hald Andersen
    • 1
  • Per thor Straten
    • 1
  1. 1.Tumor Immunology Group, Danish Cancer SocietyInstitute for Cancer BiologyCopenhagenDenmark
  2. 2.Department of OncologyHerlev University HospitalHerlevDenmark
  3. 3.Department of DermatologyUniversity of WürzburgWürzburgGermany
  4. 4.BiocentrumTechnical University of DenmarkCopenhagenDenmark

Personalised recommendations