Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Jan 1;84(1):94–99. doi: 10.1054/bjoc.2000.1547

Mapping the HLA-A24-restricted T-cell epitope peptide from a tumour-associated antigen HER2 / neu: possible immunotherapy for colorectal carcinomas

H Tanaka 1, T Tsunoda 1,2, I Nukaya 3, A Sette 3, K Matsuda 1, Y Umano 1, H Yamaue 1, K Takesako 3, H Tanimura 1
PMCID: PMC2363616  PMID: 11139320

Abstract

HER2 / neu is a potential antigen candidate for immunotherapy because of its correlation to a poor prognosis and high expressions in many kinds of epithelial tumours. Especially in the colorectal carcinomas, the higher expression of HER2 / neu is recognized in metastatic regions as well as in primary sites. Several CTL epitopes restricted by HLA-A2.1 and -A3 were identified so far, however epitopes restricted by HLA-A24, that is one of the most common allele in Japanese and Caucasians, have not been identified. In this paper, we showed identification of a CTL epitope peptide of HER2 / neu restricted by HLA-A24. HLA-A24 binding peptides selected by an analysis based on HLA-A24 binding motifs were determined for their binding affinities to HLA-A24 molecules. The peptide with a sequence of RWGLLLALL (position 8–16) named HE1 showed the highest affinity. We induced CTLs from CD8+cells of HLA-A24 healthy donors by stimulation with HE1-pulsed autologous dendritic cells. The CTLs showed cytotoxic activity against not only the peptide-pulsed target cells but also HLA-A24 colorectal tumour cell lines that endogenously overexpressed HER2 / neu. The antigen-specificity was confirmed by cold target inhibition assay using HE1-pulsed target cells. In summary, HER2 / neu peptide, RWGLLLALL, may contribute to the induction of antitumour immunity with the peptide-based immunotherapy for the colorectal carcinomas. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: CTL, epitope peptide, HER2 / neu, colorectal carcinoma

Full Text

The Full Text of this article is available as a PDF (90.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albino A. P., Jaehne J., Altorki N., Blundell M., Urmacher C., Lauwers G., Niedzwiecki D., Kelsen D. P. Amplification of HER-2/neu gene in human gastric adenocarcinomas: correlation with primary site. Eur J Surg Oncol. 1995 Feb;21(1):56–60. doi: 10.1016/s0748-7983(05)80069-1. [DOI] [PubMed] [Google Scholar]
  2. Bacus S. S., Stancovski I., Huberman E., Chin D., Hurwitz E., Mills G. B., Ullrich A., Sela M., Yarden Y. Tumor-inhibitory monoclonal antibodies to the HER-2/Neu receptor induce differentiation of human breast cancer cells. Cancer Res. 1992 May 1;52(9):2580–2589. [PubMed] [Google Scholar]
  3. Baselga J., Norton L., Albanell J., Kim Y. M., Mendelsohn J. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 1998 Jul 1;58(13):2825–2831. [PubMed] [Google Scholar]
  4. Boon T. Tumor antigens recognized by cytolytic T lymphocytes: present perspectives for specific immunotherapy. Int J Cancer. 1993 May 8;54(2):177–180. doi: 10.1002/ijc.2910540202. [DOI] [PubMed] [Google Scholar]
  5. Boon T., van der Bruggen P. Human tumor antigens recognized by T lymphocytes. J Exp Med. 1996 Mar 1;183(3):725–729. doi: 10.1084/jem.183.3.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brichard V., Van Pel A., Wölfel T., Wölfel C., De Plaen E., Lethé B., Coulie P., Boon T. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med. 1993 Aug 1;178(2):489–495. doi: 10.1084/jem.178.2.489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brossart P., Stuhler G., Flad T., Stevanovic S., Rammensee H. G., Kanz L., Brugger W. Her-2/neu-derived peptides are tumor-associated antigens expressed by human renal cell and colon carcinoma lines and are recognized by in vitro induced specific cytotoxic T lymphocytes. Cancer Res. 1998 Feb 15;58(4):732–736. [PubMed] [Google Scholar]
  8. Celis E., Tsai V., Crimi C., DeMars R., Wentworth P. A., Chesnut R. W., Grey H. M., Sette A., Serra H. M. Induction of anti-tumor cytotoxic T lymphocytes in normal humans using primary cultures and synthetic peptide epitopes. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2105–2109. doi: 10.1073/pnas.91.6.2105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coussens L., Yang-Feng T. L., Liao Y. C., Chen E., Gray A., McGrath J., Seeburg P. H., Libermann T. A., Schlessinger J., Francke U. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985 Dec 6;230(4730):1132–1139. doi: 10.1126/science.2999974. [DOI] [PubMed] [Google Scholar]
  10. Date Y., Kimura A., Kato H., Sasazuki T. DNA typing of the HLA-A gene: population study and identification of four new alleles in Japanese. Tissue Antigens. 1996 Feb;47(2):93–101. doi: 10.1111/j.1399-0039.1996.tb02520.x. [DOI] [PubMed] [Google Scholar]
  11. 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. 1995 Jun 1;181(6):2109–2117. doi: 10.1084/jem.181.6.2109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hart D. N. Dendritic cells: unique leukocyte populations which control the primary immune response. Blood. 1997 Nov 1;90(9):3245–3287. [PubMed] [Google Scholar]
  13. Hu X., Chakraborty N. G., Sporn J. R., Kurtzman S. H., Ergin M. T., Mukherji B. Enhancement of cytolytic T lymphocyte precursor frequency in melanoma patients following immunization with the MAGE-1 peptide loaded antigen presenting cell-based vaccine. Cancer Res. 1996 Jun 1;56(11):2479–2483. [PubMed] [Google Scholar]
  14. Kapitanović S., Radosević S., Kapitanović M., Andelinović S., Ferencić Z., Tavassoli M., Primorać D., Sonicki Z., Spaventi S., Pavelic K. The expression of p185(HER-2/neu) correlates with the stage of disease and survival in colorectal cancer. Gastroenterology. 1997 Apr;112(4):1103–1113. doi: 10.1016/s0016-5085(97)70120-3. [DOI] [PubMed] [Google Scholar]
  15. Kawakami Y., Eliyahu S., Sakaguchi K., Robbins P. F., Rivoltini L., Yannelli J. R., Appella E., Rosenberg S. A. 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. 1994 Jul 1;180(1):347–352. doi: 10.1084/jem.180.1.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kawashima I., Tsai V., Southwood S., Takesako K., Sette A., Celis E. Identification of HLA-A3-restricted cytotoxic T lymphocyte epitopes from carcinoembryonic antigen and HER-2/neu by primary in vitro immunization with peptide-pulsed dendritic cells. Cancer Res. 1999 Jan 15;59(2):431–435. [PubMed] [Google Scholar]
  17. Kondo A., Sidney J., Southwood S., del Guercio M. F., Appella E., Sakamoto H., Celis E., Grey H. M., Chesnut R. W., Kubo R. T. Prominent roles of secondary anchor residues in peptide binding to HLA-A24 human class I molecules. J Immunol. 1995 Nov 1;155(9):4307–4312. [PubMed] [Google Scholar]
  18. Kono K., Rongcun Y., Charo J., Ichihara F., Celis E., Sette A., Appella E., Sekikawa T., Matsumoto Y., Kiessling R. Identification of HER2/neu-derived peptide epitopes recognized by gastric cancer-specific cytotoxic T lymphocytes. Int J Cancer. 1998 Oct 5;78(2):202–208. doi: 10.1002/(sici)1097-0215(19981005)78:2<202::aid-ijc14>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  19. Kubo R. T., Sette A., Grey H. M., Appella E., Sakaguchi K., Zhu N. Z., Arnott D., Sherman N., Shabanowitz J., Michel H. Definition of specific peptide motifs for four major HLA-A alleles. J Immunol. 1994 Apr 15;152(8):3913–3924. [PubMed] [Google Scholar]
  20. Lönn U., Lönn S., Nilsson B., Stenkvist B. Prognostic significance of c-erb-B2 amplification in fine-needle biopsies of breast cancer patients not operated at diagnosis. Breast Cancer Res Treat. 1996;39(2):213–220. doi: 10.1007/BF01806188. [DOI] [PubMed] [Google Scholar]
  21. Morse M. A., Coleman R. E., Akabani G., Niehaus N., Coleman D., Lyerly H. K. Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res. 1999 Jan 1;59(1):56–58. [PubMed] [Google Scholar]
  22. Mukherji B., Chakraborty N. G., Yamasaki S., Okino T., Yamase H., Sporn J. R., Kurtzman S. K., Ergin M. T., Ozols J., Meehan J. Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8078–8082. doi: 10.1073/pnas.92.17.8078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nestle F. O., Alijagic S., Gilliet M., Sun Y., Grabbe S., Dummer R., Burg G., Schadendorf D. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med. 1998 Mar;4(3):328–332. doi: 10.1038/nm0398-328. [DOI] [PubMed] [Google Scholar]
  24. Nukaya I., Yasumoto M., Iwasaki T., Ideno M., Sette A., Celis E., Takesako K., Kato I. Identification of HLA-A24 epitope peptides of carcinoembryonic antigen which induce tumor-reactive cytotoxic T lymphocyte. Int J Cancer. 1999 Jan 5;80(1):92–97. doi: 10.1002/(sici)1097-0215(19990105)80:1<92::aid-ijc18>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  25. Peoples G. E., Goedegebuure P. S., Smith R., Linehan D. C., Yoshino I., Eberlein T. J. Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):432–436. doi: 10.1073/pnas.92.2.432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Reeves M. E., Royal R. E., Lam J. S., Rosenberg S. A., Hwu P. Retroviral transduction of human dendritic cells with a tumor-associated antigen gene. Cancer Res. 1996 Dec 15;56(24):5672–5677. [PubMed] [Google Scholar]
  27. Riddell S. R., Elliott M., Lewinsohn D. A., Gilbert M. J., Wilson L., Manley S. A., Lupton S. D., Overell R. W., Reynolds T. C., Corey L. T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat Med. 1996 Feb;2(2):216–223. doi: 10.1038/nm0296-216. [DOI] [PubMed] [Google Scholar]
  28. Romani N., Gruner S., Brang D., Kämpgen E., Lenz A., Trockenbacher B., Konwalinka G., Fritsch P. O., Steinman R. M., Schuler G. Proliferating dendritic cell progenitors in human blood. J Exp Med. 1994 Jul 1;180(1):83–93. doi: 10.1084/jem.180.1.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rosenberg S. A., Yang J. C., Schwartzentruber D. J., Hwu P., Marincola F. M., Topalian S. L., Restifo N. P., Dudley M. E., Schwarz S. L., Spiess P. J. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med. 1998 Mar;4(3):321–327. doi: 10.1038/nm0398-321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Slamon D. J., Godolphin W., Jones L. A., Holt J. A., Wong S. G., Keith D. E., Levin W. J., Stuart S. G., Udove J., Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. doi: 10.1126/science.2470152. [DOI] [PubMed] [Google Scholar]
  31. Tsai C. M., Yu D., Chang K. T., Wu L. H., Perng R. P., Ibrahim N. K., Hung M. C. Enhanced chemoresistance by elevation of p185neu levels in HER-2/neu-transfected human lung cancer cells. J Natl Cancer Inst. 1995 May 3;87(9):682–684. doi: 10.1093/jnci/87.9.682. [DOI] [PubMed] [Google Scholar]
  32. Tsai V., Southwood S., Sidney J., Sakaguchi K., Kawakami Y., Appella E., Sette A., Celis E. Identification of subdominant CTL epitopes of the GP100 melanoma-associated tumor antigen by primary in vitro immunization with peptide-pulsed dendritic cells. J Immunol. 1997 Feb 15;158(4):1796–1802. [PubMed] [Google Scholar]
  33. Tsang K. Y., Zaremba S., Nieroda C. A., Zhu M. Z., Hamilton J. M., Schlom J. Generation of human cytotoxic T cells specific for human carcinoembryonic antigen epitopes from patients immunized with recombinant vaccinia-CEA vaccine. J Natl Cancer Inst. 1995 Jul 5;87(13):982–990. doi: 10.1093/jnci/87.13.982. [DOI] [PubMed] [Google Scholar]
  34. Walter E. A., Greenberg P. D., Gilbert M. J., Finch R. J., Watanabe K. S., Thomas E. D., Riddell S. R. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995 Oct 19;333(16):1038–1044. doi: 10.1056/NEJM199510193331603. [DOI] [PubMed] [Google Scholar]
  35. Ward R. L., Hawkins N. J., Coomber D., Disis M. L. Antibody immunity to the HER-2/neu oncogenic protein in patients with colorectal cancer. Hum Immunol. 1999 Jun;60(6):510–515. doi: 10.1016/s0198-8859(99)00003-8. [DOI] [PubMed] [Google Scholar]
  36. Williams T. M., Weiner D. B., Greene M. I., Maguire H. C., Jr Expression of c-erbB-2 in human pancreatic adenocarcinomas. Pathobiology. 1991;59(1):46–52. doi: 10.1159/000163614. [DOI] [PubMed] [Google Scholar]
  37. Xia W., Lau Y. K., Zhang H. Z., Liu A. R., Li L., Kiyokawa N., Clayman G. L., Katz R. L., Hung M. C. Strong correlation between c-erbB-2 overexpression and overall survival of patients with oral squamous cell carcinoma. Clin Cancer Res. 1997 Jan;3(1):3–9. [PubMed] [Google Scholar]
  38. Yamamoto T., Ikawa S., Akiyama T., Semba K., Nomura N., Miyajima N., Saito T., Toyoshima K. Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature. 1986 Jan 16;319(6050):230–234. doi: 10.1038/319230a0. [DOI] [PubMed] [Google Scholar]
  39. Yoshino I., Peoples G. E., Goedegebuure P. S., Maziarz R., Eberlein T. J. Association of HER2/neu expression with sensitivity to tumor-specific CTL in human ovarian cancer. J Immunol. 1994 Mar 1;152(5):2393–2400. [PubMed] [Google Scholar]
  40. van der Bruggen P., Traversari C., Chomez P., Lurquin C., De Plaen E., Van den Eynde B., Knuth A., Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991 Dec 13;254(5038):1643–1647. doi: 10.1126/science.1840703. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES