Spontaneous T-cell responses against peptides derived from the Taxol resistance–associated gene-3 (TRAG-3) protein in cancer patients
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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.
KeywordsCancer-testis antigen Chemotherapy Peptide Tumor-associated antigen Tumor-specfic T cell
This work was supported by the EU project “European Searchable Tumour Cell line Database” (ESTDAB), (QLRI-CT-2001-01325), and by grants from The Novo Nordisk Foundation, The Danish Cancer Society, The Danish Research Council, Danish Foundation for Cancer Research, and the Julie von Müllens fund. We thank Professor A. Svejgaard and Ms Bodil K. Jakobsen, Department of Clinical Immunology, University Hospital, Copenhagen, for HLA-typing of patient blood samples.
- 1.Andersen MH, thor Straten P (2002) Survivin—a universal tumor antigen. Pathol Histopathol 17(2):669–675Google Scholar
- 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
- 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
- 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
- 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
- 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.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
- 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
- 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.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
- 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