Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Timeline
  • Published:

Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy

Abstract

In this Timeline, we describe the characteristics of tumour antigens that are recognized by spontaneous T cell responses in cancer patients and the paths that led to their identification. We explain on what genetic basis most, but not all, of these antigens are tumour specific: that is, present on tumour cells but not on normal cells. We also discuss how strategies that target these tumour-specific antigens can lead either to tumour-specific or to crossreactive T cell responses, which is an issue that has important safety implications in immunotherapy. These safety issues are even more of a concern for strategies targeting antigens that are not known to induce spontaneous T cell responses in patients.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2: Processing of tumour antigens that are recognized by CD8+ T cells.
Figure 3: Classes of human tumour antigens that are recognized by T lymphocytes.

References

  1. Klein, G. & Klein, E. Immune surveillance against virus-induced tumors and nonrejectability of spontaneous tumors: contrasting consequences of host versus tumor evolution. Proc. Natl Acad. Sci. USA 74, 2121–2125 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gross, L. Intradermal immunization of C3H mice against a sarcoma that originated in an animal of the same line. Cancer Res. 3, 326–333 (1943).

    Google Scholar 

  3. Prehn, R. T. & Main, J. M. Immunity to methylcholanthrene-induced sarcomas. J. Natl Cancer Inst. 18, 769–778 (1957).

    CAS  PubMed  Google Scholar 

  4. Hewitt, H. B., Blake, E. R. & Walder, A. S. A critique of the evidence for active host defence against cancer, based on personal studies of 27 murine tumours of spontaneous origin. Br. J. Cancer 33, 241–259 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Boon, T. & Kellermann, O. Rejection by syngeneic mice of cell variants obtained by mutagenesis of a malignant teratocarcinoma cell line. Proc. Natl Acad. Sci. USA 74, 272–275 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Boon, T., Kellermann, O., Mathy, E. & Gaillard, J. A. in Teratomas and Differentiation (eds Sherman, M. & Solter, D.) 161–166 (Academic Press, 1975).

    Google Scholar 

  7. Boon, T. & Van Pel, A. Teratocarcinoma cell variants rejected by syngeneic mice: protection of mice immunized with these variants against other variants and against the original malignant cell line. Proc. Natl Acad. Sci. USA 75, 1519–1523 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Van Pel, A. & Boon, T. Protection against a nonimmunogenic mouse leukemia by an immunogenic variant obtained by mutagenesis. Proc. Natl Acad. Sci. USA 79, 4718–4722 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Claman, H. N., Chaperon, E. A. & Triplett, R. F. Thymus-marrow cell combinations. synergism in antibody production. Proc. Soc. Exp. Biol. Med. 122, 1167–1171 (1966).

    Article  CAS  PubMed  Google Scholar 

  10. Miller, J. F. A. P. & Mitchell, G. F. The thymus and the precursors of antigen reactive cells. Nature 216, 659–663 (1967).

    Article  CAS  PubMed  Google Scholar 

  11. Cerottini, J. C. & Brunner, K. T. Cell-mediated cytotoxicity, allograft rejection, and tumor immunity. Adv. Immunol. 18, 67–132 (1974).

    Article  CAS  PubMed  Google Scholar 

  12. Rouse, B. T., Rollinghoff, M. & Warner, N. L. Anti-theta serum-induced supression of the cellular transfer of tumour-specific immunity to a syngeneic plasma cell tumour. Nature New Biol. 238, 116–117 (1972).

    Article  CAS  PubMed  Google Scholar 

  13. Uyttenhove, C., Van Snick, J. & Boon, T. Immunogenic variants obtained by mutagenesis of mouse mastocytoma P815. I. Rejection by syngeneic mice. J. Exp. Med. 152, 1175–1183 (1980).

    Article  CAS  PubMed  Google Scholar 

  14. Boon, T., Van Snick, J., Van Pel, A., Uyttenhove, C. & Marchand, M. Immunogenic variants obtained by mutagenesis of mouse mastocytoma P815. II. T lymphocyte-mediated cytolysis. J. Exp. Med. 152, 1184–1193 (1980).

    Article  CAS  PubMed  Google Scholar 

  15. Gillis, S. & Smith, K. A. Long term culture of tumour-specific cytotoxic T cells. Nature 268, 154–156 (1977).

    Article  CAS  PubMed  Google Scholar 

  16. Maryanski, J. L., Van Snick, J., Cerottini, J. C. & Boon, T. Immunogenic variants obtained by mutagenesis of mouse mastocytoma P815. III. Clonal analysis of the syngeneic cytolytic T lymphocyte response. Eur. J. Immunol. 12, 401–406 (1982).

    Article  CAS  PubMed  Google Scholar 

  17. Maryanski, J. L., Marchand, M., Uyttenhove, C. & Boon, T. Immunogenic variants obtained by mutagenesis of mouse mastocytoma P815. VI. Occasional escape from host rejection due to antigen-loss secondary variants. Int. J. Cancer 31, 119–123 (1983).

    Article  CAS  PubMed  Google Scholar 

  18. Uyttenhove, C., Maryanski, J. & Boon, T. Escape of mouse mastocytoma P815 after nearly complete rejection is due to antigen-loss variants rather than immunosuppression. J. Exp. Med. 157, 1040–1052 (1983).

    Article  CAS  PubMed  Google Scholar 

  19. Wheelock, E. F., Weinhold, K. J. & Levich, J. The tumor dormant state. Adv. Cancer Res. 34, 107–140 (1981).

    Article  CAS  PubMed  Google Scholar 

  20. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunol. 3, 991–998 (2002).

    Article  CAS  Google Scholar 

  21. Zinkernagel, R. M. & Doherty, P. C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248, 701–702 (1974).

    Article  CAS  PubMed  Google Scholar 

  22. Townsend, A. R. M. et al. The epitopes of Influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell 44, 959–968 (1986).

    Article  CAS  PubMed  Google Scholar 

  23. Bjorkman, P. et al. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329, 506 (1987).

    Article  CAS  PubMed  Google Scholar 

  24. Van Pel, A., De Plaen, E. & Boon, T. Selection of highly transfectable variant from mouse mastocytoma P815. Somat Cell. Mol. Genet. 11, 467–475 (1985).

    Article  CAS  PubMed  Google Scholar 

  25. De Plaen, E. et al. Immunogenic (tum) variants of mouse tumor P815: cloning of the gene of tum antigen P91A and identification of the tum mutation. Proc. Natl Acad. Sci. USA 85, 2274–2278 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lurquin, C. et al. Structure of the gene of tum transplantation antigen P91A: the mutated exon encodes a peptide recognized with Ld by cytolytic T cells. Cell 58, 293–303 (1989).

    Article  CAS  PubMed  Google Scholar 

  27. Szikora, J. P. et al. Structure of the gene of tum transplantation antigen P35B: presence of a point mutation in the antigenic allele. EMBO J. 9, 1041–1050 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sibille, C. et al. Structure of the gene of tum transplantation antigen P198: a point mutation generates a new antigenic peptide. J. Exp. Med. 172, 35–45 (1990).

    Article  CAS  PubMed  Google Scholar 

  29. Van den Eynde, B., Lethe, B., Van Pel, A., De Plaen, E. & Boon, T. The gene coding for a major tumor rejection antigen of tumor P815 is identical to the normal gene of syngeneic DBA/2 mice. J. Exp. Med. 173, 1373–1384 (1991).

    Article  CAS  PubMed  Google Scholar 

  30. Ramarathinam, L. et al. Multiple lineages of tumors express a common tumor antigen, P1A, but they are not cross-protected. J. Immunol. 155, 5323–5329 (1995).

    CAS  PubMed  Google Scholar 

  31. Boon, T. et al. Genes coding for tumor-specific rejection antigens. Cold Spring Harb. Symp. Quant. Biol. 59, 617–622 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Brandle, D. et al. The shared tumor-specific antigen encoded by mouse gene P1A is a target not only for cytolytic T lymphocytes but also for tumor rejection. Eur. J. Immunol. 28, 4010–4019 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Livingston, P. O. et al. Cell-mediated cytotoxicity for cultured autologous melanoma cells. Int. J. Cancer 24, 34–44 (1979).

    Article  CAS  PubMed  Google Scholar 

  34. Vanky, F. & Klein, E. Specificity of auto-tumor cytotoxicity exerted by fresh, activated and propagated human T lymphocytes. Int. J. Cancer 29, 547–553 (1982).

    Article  CAS  PubMed  Google Scholar 

  35. Vose, B. M. & Bonnard, G. D. Specific cytotoxicity against autologous tumour and proliferative responses of human lymphocytes grown in interleukin 2. Int. J. Cancer 29, 33–39 (1982).

    Article  CAS  PubMed  Google Scholar 

  36. Knuth, A., Danowski, B., Oettgen, H. F. & Old, L. J. T-cell-mediated cytotoxicity against autologous malignant melanoma: analysis with interleukin 2-dependent T-cell cultures. Proc. Natl Acad. Sci. USA 81, 3511–3515 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rosenberg, S. A. et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N. Engl. J. Med. 319, 1676–1680 (1988).

    Article  CAS  PubMed  Google Scholar 

  38. Hérin, M. et al. Production of stable cytolytic T-cell clones directed against autologous human melanoma. Int. J. Cancer 39, 390–396 (1987).

    Article  PubMed  Google Scholar 

  39. Van den Eynde, B. et al. Presence on a human melanoma of multiple antigens recognized by autologous CTL. Int. J. Cancer 44, 634–640 (1989).

    Article  CAS  PubMed  Google Scholar 

  40. van der Bruggen, P. et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254, 1643–1647 (1991).

    Article  CAS  PubMed  Google Scholar 

  41. Fiszer, D. & Kurpisz, M. Major histocompatibility complex expression on human, male germ cells: a review. Am. J. Reprod. Immunol. 40, 172–176 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Traversari, C. et al. A nonapeptide encoded by human gene MAGE-1 is recognized on HLA-A1 by cytolytic T lymphocytes directed against tumor antigen MZ2-E. J. Exp. Med. 176, 1453–1457 (1992).

    Article  CAS  PubMed  Google Scholar 

  43. De Plaen, E. et al. Structure, chromosomal localization, and expression of 12 genes of the MAGE family. Immunogenetics 40, 360–369 (1994).

    Article  CAS  PubMed  Google Scholar 

  44. Lurquin, C. et al. Two members of the human MAGEB gene family located in Xp21.3 are expressed in tumors of various histological origins. Genomics 46, 397–408 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Muscatelli, F., Walker, A. P., De Plaen, E., Stafford, A. N. & Monaco, A. P. Isolation and characterization of a MAGE gene family in the Xp21.3 region. Proc. Natl Acad. Sci. USA 92, 4987–4991 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lucas, S., De Plaen, E. & Boon, T. MAGE-B5, MAGE-B6, MAGE-C2, and MAGE-C3: four new members of the MAGE family with tumor-specific expression. Int. J. Cancer 87, 55–60 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Lucas, S. et al. Identification of a new MAGE gene with tumor-specific expression by representational difference analysis. Cancer Res. 58, 743–752 (1998).

    CAS  PubMed  Google Scholar 

  48. Boël, P. et al. BAGE: a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity 2, 167–175 (1995).

    Article  PubMed  Google Scholar 

  49. Van den Eynde, B. et al. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J. Exp. Med. 182, 689–698 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Coulie, P. G. et al. A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Proc. Natl Acad. Sci. USA 92, 7976–7980 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wölfel, T. et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269, 1281–1284 (1995).

    Article  PubMed  Google Scholar 

  52. Brandle, D., Brasseur, F., Weynants, P., Boon, T. & Van den Eynde, B. A mutated HLA-A2 molecule recognized by autologous cytotoxic T lymphocytes on a human renal cell carcinoma. J. Exp. Med. 183, 2501–2508 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Robbins, P. F. et al. A mutated β-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J. Exp. Med. 183, 1185–1192 (1996).

    Article  CAS  PubMed  Google Scholar 

  54. Brichard, V. et al. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J. Exp. Med. 178, 489–495 (1993).

    Article  CAS  PubMed  Google Scholar 

  55. Topalian, S. L. et al. Melanoma-specific CD4+T cells recognize nonmutated HLA-DR-restricted tyrosinase epitopes. J. Exp. Med. 183, 1965–1971 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Sahin, U. et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl Acad. Sci. USA 92, 11810–11813 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Smith, H. A. & McNeel, D. G. The SSX family of cancer-testis antigens as target proteins for tumor therapy. Clin. Dev. Immunol. 2010, 150591 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chen, Y. T. et al. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc. Natl Acad. Sci. USA 94, 1914–1918 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen, Y.-T. Identification of human tumor antigens by serological expression cloning: an online review on SEREX. Cancer Immun. [online], (2004).

  60. Rotzschke, O. et al. Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature 348, 252–254 (1990).

    Article  CAS  PubMed  Google Scholar 

  61. Cox, A. L. et al. Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science 264, 716–719 (1994).

    Article  CAS  PubMed  Google Scholar 

  62. Skipper, J. C. et al. An HLA-A2-restricted tyrosinase antigen on melanoma cells results from posttranslational modification and suggests a novel pathway for processing of membrane proteins. J. Exp. Med. 183, 527–534 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Dalet, A. et al. An antigenic peptide produced by reverse splicing and double asparagine deamidation. Proc. Natl Acad. Sci. USA 108, E323–E331 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Parker, K. C., Bednarek, M. A. & Coligan, J. E. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J. Immunol. 152, 163–175 (1994).

    CAS  PubMed  Google Scholar 

  65. Rammensee, H.-G., Bachmann, J. & Stevanović, S. MHC Ligands and Peptide Motifs (Springer, 1997).

    Book  Google Scholar 

  66. van der Bruggen, P. et al. A peptide encoded by human gene MAGE-3 and presented by HLA-A2 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE-3. Eur. J. Immunol. 24, 3038–3043 (1994).

    Article  CAS  PubMed  Google Scholar 

  67. Chaux, P. et al. Identification of five MAGE-A1 epitopes recognized by cytolytic T lymphocytes obtained by in vitro stimulation with dendritic cells transduced with MAGE-A1. J. Immunol. 163, 2928–2936 (1999).

    CAS  PubMed  Google Scholar 

  68. Chaux, P. et al. Identification of MAGE-3 epitopes presented by HLA-DR molecules to CD4+ T lymphocytes. J. Exp. Med. 189, 767–778 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. van der Bruggen, P. et al. Tumor-specific shared antigenic peptides recognized by human T cells. Immunol. Rev. 188, 51–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Gambacorti-Passerini, C. et al. Human CD4 lymphocytes specifically recognize a peptide representing the fusion region of the hybrid protein pml/RAR α present in acute promyelocytic leukemia cells. Blood 81, 1369–1375 (1993).

    CAS  PubMed  Google Scholar 

  71. ten Bosch, G. J., Joosten, A. M., Kessler, J. H., Melief, C. J. & Leeksma, O. C. Recognition of BCR-ABL positive leukemic blasts by human CD4+ T cells elicited by primary in vitro immunization with a BCR-ABL breakpoint peptide. Blood 88, 3522–3527 (1996).

    CAS  Google Scholar 

  72. Tsang, K. Y. et al. Generation of human cytotoxic T cells specific for human carcinoembryonic antigen epitopes from patients immunized with recombinant vaccinia-CEA vaccine. J. Natl Cancer Inst. 87, 982–990 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. van der Bruggen, P., Stroobant, V., Vigneron, N. & Van den Eynde, B. Peptide database: T cell-defined tumor antigens. Cancer Immun. [online], (2013).

  74. Long, H. M., Parsonage, G., Fox, C. P. & Lee, S. P. Immunotherapy for Epstein-Barr virus-associated malignancies. Drug News Perspect. 23, 221–228 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. van der Burg, S. H. & Melief, C. J. Therapeutic vaccination against human papilloma virus induced malignancies. Curr. Opin. Immunol. 23, 252–257 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Fujita, Y., Rooney, C. M. & Heslop, H. E. Adoptive cellular immunotherapy for viral diseases. Bone Marrow Transplant. 41, 193–198 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Ramos, J. C. & Lossos, I. S. Newly emerging therapies targeting viral-related lymphomas. Curr. Oncol. Rep. 13, 416–426 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lennerz, V. et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc. Natl Acad. Sci. USA 102, 16013–16018 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Network, C. G. A. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

    Article  CAS  Google Scholar 

  80. Mandruzzato, S., Brasseur, F., Andry, G., Boon, T. & van der Bruggen, P. A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma. J. Exp. Med. 186, 785–793 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yotnda, P. et al. Cytotoxic T cell response against the chimeric p210 BCR-ABL protein in patients with chronic myelogenous leukemia. J. Clin. Invest. 101, 2290–2296 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yotnda, P. et al. Cytotoxic T cell response against the chimeric ETV6-AML1 protein in childhood acute lymphoblastic leukemia. J. Clin. Invest. 102, 455–462 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Makita, M. et al. Leukemia-associated fusion proteins, dek-can and bcr-abl, represent immunogenic HLA-DR-restricted epitopes recognized by fusion peptide-specific CD4+ T lymphocytes. Leukemia 16, 2400–2407 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Yun, C. et al. Augmentation of immune response by altered peptide ligands of the antigenic peptide in a human CD4+ T-cell clone reacting to TEL/AML1 fusion protein. Tissue Antigens 54, 153–161 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Boczkowski, D., Nair, S. K., Nam, J. H., Lyerly, H. K. & Gilboa, E. Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells. Cancer Res. 60, 1028–1034 (2000).

    CAS  PubMed  Google Scholar 

  86. Van Tendeloo, V. F. et al. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood 98, 49–56 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Weber, J. et al. Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2′-deoxycytidine. Cancer Res. 54, 1766–1771 (1994).

    CAS  PubMed  Google Scholar 

  88. De Smet, C. et al. The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc. Natl Acad. Sci. USA 93, 7149–7153 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Grunau, C. et al. Frequent DNA hypomethylation of human juxtacentromeric BAGE loci in cancer. Genes Chromosomes Cancer 43, 11–24 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Gjerstorff, M. F., Kock, K., Nielsen, O. & Ditzel, H. J. MAGE-A1, GAGE and NY-ESO-1 cancer/testis antigen expression during human gonadal development. Hum. Reprod. 22, 953–960 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Wölfel, T. et al. Two tyrosinase nonapeptides recognized on HLA-A2 melanomas by autologous cytolytic T lymphocytes. Eur. J. Immunol. 24, 759–764 (1994).

    Article  PubMed  Google Scholar 

  92. Coulie, P. G. et al. A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J. Exp. Med. 180, 35–42 (1994).

    Article  CAS  PubMed  Google Scholar 

  93. Kawakami, Y. et al. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J. Exp. Med. 180, 347–352 (1994).

    Article  CAS  PubMed  Google Scholar 

  94. Kawakami, Y. et al. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc. Natl Acad. Sci. USA 91, 3515–3519 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bakker, A. B. et al. Identification of a novel peptide derived from the melanocyte-specific gp100 antigen as the dominant epitope recognized by an HLA-A2.1-restricted anti-melanoma CTL line. Int. J. Cancer 62, 97–102 (1995).

    Article  CAS  PubMed  Google Scholar 

  96. Kawakami, Y. et al. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc. Natl Acad. Sci. USA 91, 6458–6462 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Pittet, M. J. et al. High frequencies of naive Melan-A/MART-1-specific CD8+ T cells in a large proportion of human histocompatibility leukocyte antigen (HLA)-A2 individuals. J. Exp. Med. 190, 705–715 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lonchay, C. et al. Correlation between tumor regression and T cell responses in melanoma patients vaccinated with a MAGE antigen. Proc. Natl Acad. Sci. USA 101 (Suppl. 2), 14631–14638 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chaux, P., Vantomme, V., Coulie, P., Boon, T. & van der Bruggen, P. Estimation of the frequencies of anti-MAGE-3 cytolytic T-lymphocyte precursors in blood from individuals without cancer. Int. J. Cancer 77, 538–542 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Alanio, C., Lemaitre, F., Law, H. K., Hasan, M. & Albert, M. L. Enumeration of human antigen-specific naive CD8+ T cells reveals conserved precursor frequencies. Blood 115, 3718–3725 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Zippelius, A. et al. Thymic selection generates a large T cell pool recognizing a self-peptide in humans. J. Exp. Med. 195, 485–494 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Romero, P. et al. Ex vivo staining of metastatic lymph nodes by class I major histocompatibility complex tetramers reveals high numbers of antigen-experienced tumor-specific cytolytic T lymphocytes. J. Exp. Med. 188, 1641–1650 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Correale, P. et al. In vitro generation of human cytotoxic T lymphocytes specific for peptides derived from prostate-specific antigen. J. Natl Cancer Inst. 89, 293–300 (1997).

    Article  CAS  PubMed  Google Scholar 

  104. Olson, B. M. et al. HLA-A2-restricted T-cell epitopes specific for prostatic acid phosphatase. Cancer Immunol. Immunother. 59, 943–953 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Fisk, B., Blevins, T. L., Wharton, J. T. & Ioannides, C. G. Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J. Exp. Med. 181, 2109–2117 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Inoue, K. et al. Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. Blood 89, 1405–1412 (1997).

    CAS  PubMed  Google Scholar 

  107. Cilloni, D. et al. Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia 16, 2115–2121 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Chapuis, A. G. et al. Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients. Sci. Transl. Med. 5, 174ra27 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Vlad, A. M., Kettel, J. C., Alajez, N. M., Carlos, C. A. & Finn, O. J. MUC1 immunobiology: from discovery to clinical applications. Adv. Immunol. 82, 249–293 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Giraud, M. et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448, 934–937 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Gotter, J., Brors, B., Hergenhahn, M. & Kyewski, B. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J. Exp. Med. 199, 155–166 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Huijbers, I. J. et al. Minimal tolerance to a tumor antigen encoded by a cancer-germline gene. J. Immunol. 188, 111–121 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Weber, J. S., Kahler, K. C. & Hauschild, A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30, 2691–2697 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Morgan, R. A. et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 36, 133–151 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Linette, G. P. et al. Cardiovascular toxicity and titin cross-reactivity of affinity enhanced T cells in myeloma and melanoma. Blood 122, 863–871 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Parkhurst, M. R. et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19, 620–626 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Lamers, C. H. et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J. Clin. Oncol. 24, e20–e22 (2006).

    Article  PubMed  Google Scholar 

  118. Quaglino, P. et al. Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study. Ann. Oncol. 21, 409–414 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Khammari, A. et al. Long-term follow-up of patients treated by adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol. Immunother. 56, 1853–1860 (2007).

    Article  PubMed  Google Scholar 

  120. Yeh, S. et al. Ocular and systemic autoimmunity after successful tumor-infiltrating lymphocyte immunotherapy for recurrent, metastatic melanoma. Ophthalmology 116, 981–989 (2009).

    Article  PubMed  Google Scholar 

  121. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Blattman, J. N. & Greenberg, P. D. Cancer immunotherapy: a treatment for the masses. Science 305, 200–205 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Gattinoni, L., Powell, D. J. Jr, Rosenberg, S. A. & Restifo, N. P. Adoptive immunotherapy for cancer: building on success. Nature Rev. Immunol. 6, 383–393 (2006).

    Article  CAS  Google Scholar 

  126. Germeau, C. et al. High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens. J. Exp. Med. 201, 241–248 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lurquin, C. et al. Contrasting frequencies of antitumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen. J. Exp. Med. 201, 249–257 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Carrasco, J. et al. Vaccination of a melanoma patient with mature dendritic cells pulsed with MAGE-3 peptides triggers the activity of nonvaccine anti-tumor cells. J. Immunol. 180, 3585–3593 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Coulie, P. G. et al. Precursor frequency analysis of human cytolytic T lymphocytes directed against autologous melanoma cells. Int. J. Cancer 50, 289–297 (1992).

    Article  CAS  PubMed  Google Scholar 

  130. Boon, T., Coulie, P. G., Van den Eynde, B. J. & van der Bruggen, P. Human T cell responses against melanoma. Annu. Rev. Immunol. 24, 175–208 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Gajewski, T. F. et al. Immune resistance orchestrated by the tumor microenvironment. Immunol. Rev. 213, 131–145 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Guillaume, B. et al. Two abundant proteasome subtypes that uniquely process some antigens presented by HLA class I molecules. Proc. Natl Acad. Sci. USA 107, 18599–18604 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Morel, S. et al. Processing of some antigens by the standard proteasome but not by the immunoproteasome results in poor presentation by dendritic cells. Immunity 12, 107–117 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Schultz, E. S. et al. The production of a new MAGE-3 peptide presented to cytolytic T lymphocytes by HLA-B40 requires the immunoproteasome. J. Exp. Med. 195, 391–399 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chapiro, J. et al. Destructive cleavage of antigenic peptides either by the immunoproteasome or by the standard proteasome results in differential antigen presentation. J. Immunol. 176, 1053–1061 (2006).

    Article  CAS  PubMed  Google Scholar 

  136. Guillaume, B. et al. Analysis of the processing of seven human tumor antigens by intermediate proteasomes. J. Immunol. 189, 3538–3547 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. Hanada, K., Yewdell, J. W. & Yang, J. C. Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature 427, 252–256 (2004).

    Article  CAS  PubMed  Google Scholar 

  138. Vigneron, N. et al. An antigenic peptide produced by peptide splicing in the proteasome. Science 304, 587–590 (2004).

    Article  CAS  PubMed  Google Scholar 

  139. Parmentier, N. et al. Production of an antigenic peptide by insulin-degrading enzyme. Nature Immunol. 11, 449–454 (2010).

    Article  CAS  Google Scholar 

  140. Kessler, J. H. et al. Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes. Nature Immunol. 12, 45–53 (2011).

    Article  CAS  Google Scholar 

  141. Rogner, U. C., Wilke, K., Steck, E., Korn, B. & Poustka, A. The melanoma antigen gene (MAGE) family is clustered in the chromosomal band Xq28. Genomics 29, 725–731 (1995).

    Article  CAS  PubMed  Google Scholar 

  142. Doyle, J. M., Gao, J., Wang, J., Yang, M. & Potts, P. R. MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol. Cell 39, 963–974 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Monte, M. et al. MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents. Proc. Natl Acad. Sci. USA 103, 11160–11165 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Yang, B. et al. MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. Cancer Res. 67, 9954–9962 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Bai, S., He, B. & Wilson, E. M. Melanoma antigen gene protein MAGE-11 regulates androgen receptor function by modulating the interdomain interaction. Mol. Cell. Biol. 25, 1238–1257 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Wang, J. et al. Induced malignant genome reprogramming in somatic cells by testis-specific factors. Biochim. Biophys. Acta 1809, 221–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  147. Laduron, S. et al. MAGE-A1 interacts with adaptor SKIP and the deacetylase HDAC1 to repress transcription. Nucleic Acids Res. 32, 4340–4350 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Nagao, T. et al. MAGE-A4 interacts with the liver oncoprotein gankyrin and suppresses its tumorigenic activity. J. Biol. Chem. 278, 10668–10774 (2003).

    Article  CAS  PubMed  Google Scholar 

  149. Peikert, T., Specks, U., Farver, C., Erzurum, S. C. & Comhair, S. A. Melanoma antigen A4 is expressed in non-small cell lung cancers and promotes apoptosis. Cancer Res. 66, 4693–4700 (2006).

    Article  CAS  PubMed  Google Scholar 

  150. Gaugler, B. et al. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J. Exp. Med. 179, 921–930 (1994).

    Article  CAS  PubMed  Google Scholar 

  151. Duffour, M.-T. et al. A MAGE-A4 peptide presented by HLA-A2 is recognized by cytolytic T lymphocytes. Eur. J. Immunol. 29, 3329–3337 (1999).

    Article  CAS  PubMed  Google Scholar 

  152. Panelli, M. C. et al. A tumor-infiltrating lymphocyte from a melanoma metastasis with decreased expression of melanoma differentiation antigens recognizes MAGE-12. J. Immunol. 164, 4382–4392 (2000).

    Article  CAS  PubMed  Google Scholar 

  153. Ma, W. et al. Two new tumor-specific antigenic peptides encoded by gene MAGE-C2 and presented to cytolytic T lymphocytes by HLA-A2. Int. J. Cancer 109, 698–702 (2004).

    Article  CAS  PubMed  Google Scholar 

  154. Ruault, M. et al. New BAGE (B melanoma antigen) genes mapping to the juxtacentromeric regions of human chromosomes 13 and 21 have a cancer/testis expression profile. Eur. J. Hum. Genet. 10, 833–840 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Ruault, M. et al. BAGE genes generated by juxtacentromeric reshuffling in the Hominidae lineage are under selective pressure. Genomics 81, 391–399 (2003).

    Article  CAS  PubMed  Google Scholar 

  156. Gjerstorff, M. F. & Ditzel, H. J. An overview of the GAGE cancer/testis antigen family with the inclusion of newly identified members. Tissue Antigens 71, 187–192 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Cilensek, Z. M., Yehiely, F., Kular, R. K. & Deiss, L. P. A member of the GAGE family of tumor antigens is an anti-apoptotic gene that confers resistance to Fas/CD95/APO-1, Interferon-γ, taxol and γ-irradiation. Cancer Biol. Ther. 1, 380–387 (2002).

    Article  CAS  PubMed  Google Scholar 

  158. Zendman, A. J., Van Kraats, A. A., Weidle, U. H., Ruiter, D. J. & Van Muijen, G. N. The XAGE family of cancer/testis-associated genes: alignment and expression profile in normal tissues, melanoma lesions and Ewing's sarcoma. Int. J. Cancer 99, 361–369 (2002).

    Article  CAS  PubMed  Google Scholar 

  159. Shimono, M. et al. Identification of DR9-restricted XAGE antigen on lung adenocarcinoma recognized by autologous CD4 T-cells. Int. J. Oncol. 30, 835–840 (2007).

    CAS  PubMed  Google Scholar 

  160. Jager, E. et al. 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 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Chen, Y. T. et al. Identification of multiple cancer/testis antigens by allogeneic antibody screening of a melanoma cell line library. Proc. Natl Acad. Sci. USA 95, 6919–6923 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Güre, A. O., Wei, I. J., Old, L. J. & Chen, Y. T. The SSX gene family: characterization of 9 complete genes. Int. J. Cancer 101, 448–453 (2002).

    Article  CAS  PubMed  Google Scholar 

  163. Lim, F. L., Soulez, M., Koczan, D., Thiesen, H. J. & Knight, J. C. A KRAB-related domain and a novel transcription repression domain in proteins encoded by SSX genes that are disrupted in human sarcomas. Oncogene 17, 2013–2018 (1998).

    Article  CAS  PubMed  Google Scholar 

  164. Thaete, C. et al. Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus. Hum. Mol. Genet. 8, 585–591 (1999).

    Article  CAS  PubMed  Google Scholar 

  165. Ayyoub, M. et al. Proteasome-assisted identification of a SSX-2-derived epitope recognized by tumor-reactive CTL infiltrating metastatic melanoma. J. Immunol. 168, 1717–1722 (2002).

    Article  CAS  PubMed  Google Scholar 

  166. Yang, R., Morosetti, R. & Koeffler, H. P. Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines. Cancer Res. 57, 913–920 (1997).

    CAS  PubMed  Google Scholar 

  167. Wolgemuth, D. J. Function of the A-type cyclins during gametogenesis and early embryogenesis. Results Probl. Cell Differ. 53, 391–413 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Ochsenreither, S. et al. Cyclin-A1 represents a new immunogenic targetable antigen expressed in acute myeloid leukemia stem cells with characteristics of a cancer-testis antigen. Blood 119, 5492–5501 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Fukuyama, T. et al. Identification of a new cancer/germline gene, KK-LC-1, encoding an antigen recognized by autologous CTL induced on human lung adenocarcinoma. Cancer Res. 66, 4922–4928 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Park, H. J. et al. The centrosomal localization of KM-HN-1 (MGC33607) depends on the leucine zipper motif and the C-terminal coiled-coil domain. Exp. Mol. Med. 39, 828–838 (2007).

    Article  CAS  PubMed  Google Scholar 

  171. Monji, M. et al. Identification of a novel human cancer/testis antigen, KM-HN-1, recognized by cellular and humoral immune responses. Clin. Cancer Res. 10, 6047–6057 (2004).

    Article  CAS  PubMed  Google Scholar 

  172. Martelange, V., De Smet, C., De Plaen, E., Lurquin, C. & Boon, T. Identification on a human sarcoma of two new genes with tumor-specific expression. Cancer Res. 60, 3848–3855 (2000).

    CAS  PubMed  Google Scholar 

  173. Miyahara, Y. et al. Determination of cellularly processed HLA-A2402-restricted novel CTL epitopes derived from two cancer germ line genes, MAGE-A4 and SAGE. Clin. Cancer Res. 11, 5581–5589 (2005).

    Article  CAS  PubMed  Google Scholar 

  174. Lim, S. H., Wang, Z., Chiriva-Internati, M. & Xue, Y. Sperm protein 17 is a novel cancer-testis antigen in multiple myeloma. Blood 97, 1508–1510 (2001).

    Article  CAS  PubMed  Google Scholar 

  175. Frayne, J. & Hall, L. A re-evaluation of sperm protein 17 (Sp17) indicates a regulatory role in an A-kinase anchoring protein complex, rather than a unique role in sperm-zona pellucida binding. Reproduction 124, 767–774 (2002).

    Article  CAS  PubMed  Google Scholar 

  176. Chiriva-Internati, M., Wang, Z., Pochopien, S., Salati, E. & Lim, S. H. Identification of a sperm protein 17 CTL epitope restricted by HLA-A1. Int. J. Cancer 107, 863–865 (2003).

    Article  CAS  PubMed  Google Scholar 

  177. Lucas, S., Brasseur, F. & Boon, T. A new MAGE gene with ubiquitous expression does not code for known MAGE antigens recognized by T cells. Cancer Res. 59, 4100–4103 (1999).

    CAS  PubMed  Google Scholar 

  178. Chomez, P. et al. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res. 61, 5544–5551 (2001).

    CAS  PubMed  Google Scholar 

  179. Alpen, B., Gure, A. O., Scanlan, M. J., Old, L. J. & Chen, Y. T. A new member of the NY-ESO-1 gene family is ubiquitously expressed in somatic tissues and evolutionarily conserved. Gene 297, 141–149 (2002).

    Article  CAS  PubMed  Google Scholar 

  180. Egland, K. A., Kumar, V., Duray, P. & Pastan, I. Characterization of overlapping XAGE-1 transcripts encoding a cancer testis antigen expressed in lung, breast, and other types of cancers. Mol. Cancer Ther. 1, 441–450 (2002).

    CAS  PubMed  Google Scholar 

  181. Türeci, Ö. et al. The SSX-2 gene, which is involved in the t(X;18) translocation of synovial sarcomas, codes for the human tumor antigen HOM-MEL-40. Cancer Res. 56, 4766–4772 (1996).

    PubMed  Google Scholar 

  182. Smith, H. A., Cronk, R. J., Lang, J. M. & McNeel, D. G. Expression and immunotherapeutic targeting of the SSX family of cancer-testis antigens in prostate cancer. Cancer Res. 71, 6785–6795 (2011).

    Article  CAS  PubMed  Google Scholar 

  183. Brunner, K. T., Mauel, J., Cerottini, J.-C. & Chapuis, B. Quantitative assay of the lytic action of immune lymphoid cells on 51cr-labelled allogeneic target cells in vitro; inhibition by isoantibody and by drugs. Immunology 14, 181–196 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Holm, G. & Perlmann, P. Quantitative studies on phytohaemagglutinin-induced cytotoxicity by human lymphocytes against homologous cells in tissue culture. Immunology 12, 525–536 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Levy, J. P. & Leclerc, J. C. The murine sarcoma virus-induced tumor: exception or general model in tumor immunology? Adv. Cancer Res. 24, 1–66 (1977).

    Article  CAS  PubMed  Google Scholar 

  186. Bjorkman, P. J. et al. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329, 512–518 (1987).

    Article  CAS  PubMed  Google Scholar 

  187. Topalian, S. L. et al. Human CD4+ T cells specifically recognize a shared melanoma-associated antigen encoded by the tyrosinase gene. Proc. Natl Acad. Sci. USA 91, 9461–9465 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Lethé, B. et al. LAGE-1, a new gene with tumor specificity. Int. J. Cancer 76, 903–908 (1998).

    Article  PubMed  Google Scholar 

  189. Guilloux, Y. et al. A peptide recognized by human cytolytic T lymphocytes on HLA-A2 melanomas is encoded by an intron sequence of the N-acetylglucosaminyltransferase V gene. J. Exp. Med. 183, 1173–1183 (1996).

    Article  CAS  PubMed  Google Scholar 

  190. Wang, R. F., Parkhurst, M. R., Kawakami, Y., Robbins, P. F. & Rosenberg, S. A. Utilization of an alternative open reading frame of a normal gene in generating a novel human cancer antigen. J. Exp. Med. 183, 1131–1140 (1996).

    Article  CAS  PubMed  Google Scholar 

  191. Lupetti, R. et al. Translation of a retained intron in tyrosinase-related protein (TRP)-2 mRNA generates a new cytotoxic T lymphocyte (CTL)-defined and shared human melanoma antigen not expressed in normal cells of the melanocytic lineage. J. Exp. Med. 188, 1005–1016 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Van den Eynde, B. J. et al. A new antigen recognized by cytolytic T lymphocytes on a human kidney tumor results from reverse strand transcription. J. Exp. Med. 190, 1793–1800 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Aarnoudse, C. A., van den Doel, P. B., Heemskerk, B. & Schrier, P. I. Interleukin-2-induced, melanoma-specific T cells recognize CAMEL, an unexpected translation product of LAGE-1. Int. J. Cancer 82, 442–448 (1999).

    Article  CAS  PubMed  Google Scholar 

  194. Probst-Kepper, M. et al. An alternative open reading frame of the human macrophage colony-stimulating factor gene is independently translated and codes for an antigenic peptide of 14 amino acids recognized by tumor-infiltrating CD8 T lymphocytes. J. Exp. Med. 193, 1189–1198 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Ohminami, H., Yasukawa, M. & Fujita, S. HLA class I-restricted lysis of leukemia cells by a CD8+ cytotoxic T-lymphocyte clone specific for WT1 peptide. Blood 95, 286–293 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank S. Depelchin and J. Klein for editorial work, and D. Godelaine and A. Van Pel for reviewing the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pierre G. Coulie.

Ethics declarations

Competing interests

Patents on human tumour antigens owned by the Ludwig Institute. Part of licence fees. P.G.C., T.B., B.J.V and P.V.

PowerPoint slides

Glossary

Adoptive transfer

In cancer immunotherapy, the infusion into patients of autologous antitumour T cells that have been amplified in vitro. The lymphocytes can also be transduced with retroviral expression vectors in order to express a given T cell receptor or other gene products.

Anergy

Hyporesponsiveness or unresponsiveness of T lymphocytes after recognition of their antigen.

Central tolerance

The deletion or inactivation of immature autoreactive B cells and T cells of the primary lymphoid organs: the bone marrow (B cells) and the thymus (T cells). The remaining mature autoreactive B cells and T cells are dealt with by the mechanisms of peripheral tolerance.

Deamidation

The removal of an amide group. In N-glycosylated proteins, deglycosylation of an asparagine by the peptide N-glycanase generates an aspartate by deamidation. This can result in an antigenic peptide.

Epitope

The molecular configuration of a peptide that is recognized by a T cell receptor or by an antibody.

Lymphoablation

The elimination of lymphocytes by a combination of lymphocyte-depleting chemotherapy (cyclophosphamide and fludarabine) and total body irradiation.

Serological analysis of recombinant cDNA expression libraries

(SEREX). A procedure whereby proteins from human tumours are screened for recognition by autologous serum.

Thymic epithelial cells

The thymus contains developing T lymphocytes and a stroma that consists of epithelial cells and dendritic cells. Epithelial cells of the thymic medulla, in which the transcription factor autoimmune regulator controls the expression of peripheral tissue antigens, contribute to the induction of central tolerance for T lymphocytes.

Uveitis

Inflammation of the uvea, which is the middle layer of the eye, between the retina and the sclera.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coulie, P., Van den Eynde, B., van der Bruggen, P. et al. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 14, 135–146 (2014). https://doi.org/10.1038/nrc3670

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3670

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer