Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Jun 1;181(6):2109–2117. doi: 10.1084/jem.181.6.2109

Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines

PMCID: PMC2192068  PMID: 7539040

Abstract

Synthetic peptide analogues of sequences in the HER-2 protooncogene (HER-2) were selected based on the presence of HLA-A2.1 anchor motifs to identify the epitopes on HER-2 recognized by ovarian tumor-reactive CTL. 19 synthetic peptides were evaluated for recognition by four HLA- A2 ovarian-specific cytotoxic T lymphocyte (CTL) lines obtained from leukocytes associated with ovarian tumors. The nonapeptide E75 (HER-2, 369-377:KIFGSLAFL) was efficient in sensitizing T2 cells for lysis by all four CTL lines. This peptide was specifically recognized by cloned CD8+ CTL isolated from one of the ovarian-specific CTL lines. E75- pulsed T2 cells inhibited lysis by the same CTL clone of both an HLA- A2+ HER-2high ovarian tumor and a HER-2high cloned ovarian tumor line transfected with HLA-A2, suggesting that this or a structurally similar epitope may be specifically recognized by these CTL on ovarian tumors. Several other HER-2 peptides were recognized preferentially by one or two CTL lines, suggesting that both common and private HER-2 epitopes may be immunogenic in patients with ovarian tumors. Since HER-2 is a self-antigen, these peptides may be useful for understanding mechanisms of tumor recognition by T cells, immunological tolerance to tumor, and structural characterization of tumor antigens.

Full Text

The Full Text of this article is available as a PDF (938.5 KB).

Selected References

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

  1. Barnd D. L., Lan M. S., Metzgar R. S., Finn O. J. Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7159–7163. doi: 10.1073/pnas.86.18.7159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bednarek M. A., Sauma S. Y., Gammon M. C., Porter G., Tamhankar S., Williamson A. R., Zweerink H. J. The minimum peptide epitope from the influenza virus matrix protein. Extra and intracellular loading of HLA-A2. J Immunol. 1991 Dec 15;147(12):4047–4053. [PubMed] [Google Scholar]
  3. Campbell I. G., Jones T. A., Foulkes W. D., Trowsdale J. Folate-binding protein is a marker for ovarian cancer. Cancer Res. 1991 Oct 1;51(19):5329–5338. [PubMed] [Google Scholar]
  4. Catipović B., Dal Porto J., Mage M., Johansen T. E., Schneck J. P. Major histocompatibility complex conformational epitopes are peptide specific. J Exp Med. 1992 Dec 1;176(6):1611–1618. doi: 10.1084/jem.176.6.1611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen Y., Sidney J., Southwood S., Cox A. L., Sakaguchi K., Henderson R. A., Appella E., Hunt D. F., Sette A., Engelhard V. H. Naturally processed peptides longer than nine amino acid residues bind to the class I MHC molecule HLA-A2.1 with high affinity and in different conformations. J Immunol. 1994 Mar 15;152(6):2874–2881. [PubMed] [Google Scholar]
  6. Cox A. L., Skipper J., Chen Y., Henderson R. A., Darrow T. L., Shabanowitz J., Engelhard V. H., Hunt D. F., Slingluff C. L., Jr Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science. 1994 Apr 29;264(5159):716–719. doi: 10.1126/science.7513441. [DOI] [PubMed] [Google Scholar]
  7. Falk K., Rötzschke O., Stevanović S., Jung G., Rammensee H. G. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature. 1991 May 23;351(6324):290–296. doi: 10.1038/351290a0. [DOI] [PubMed] [Google Scholar]
  8. Fisk B., Ioannides C. G., Aggarwal S., Wharton J. T., O'Brian C. A., Restifo N., Glisson B. S. Enhanced expression of HLA-A,B,C and inducibility of TAP-1, TAP-2, and HLA-A,B,C by interferon-gamma in a multidrug-resistant small cell lung cancer line. Lymphokine Cytokine Res. 1994 Apr;13(2):125–131. [PubMed] [Google Scholar]
  9. Gaugler B., Van den Eynde B., van der Bruggen P., Romero P., Gaforio J. J., De Plaen E., Lethé B., Brasseur F., Boon T. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J Exp Med. 1994 Mar 1;179(3):921–930. doi: 10.1084/jem.179.3.921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gendler S., Taylor-Papadimitriou J., Duhig T., Rothbard J., Burchell J. A highly immunogenic region of a human polymorphic epithelial mucin expressed by carcinomas is made up of tandem repeats. J Biol Chem. 1988 Sep 15;263(26):12820–12823. [PubMed] [Google Scholar]
  11. Henderson R. A., Michel H., Sakaguchi K., Shabanowitz J., Appella E., Hunt D. F., Engelhard V. H. HLA-A2.1-associated peptides from a mutant cell line: a second pathway of antigen presentation. Science. 1992 Mar 6;255(5049):1264–1266. doi: 10.1126/science.1546329. [DOI] [PubMed] [Google Scholar]
  12. Hogan K. T., Shimojo N., Walk S. F., Engelhard V. H., Maloy W. L., Coligan J. E., Biddison W. E. Mutations in the alpha 2 helix of HLA-A2 affect presentation but do not inhibit binding of influenza virus matrix peptide. J Exp Med. 1988 Aug 1;168(2):725–736. doi: 10.1084/jem.168.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Houbiers J. G., Nijman H. W., van der Burg S. H., Drijfhout J. W., Kenemans P., van de Velde C. J., Brand A., Momburg F., Kast W. M., Melief C. J. In vitro induction of human cytotoxic T lymphocyte responses against peptides of mutant and wild-type p53. Eur J Immunol. 1993 Sep;23(9):2072–2077. doi: 10.1002/eji.1830230905. [DOI] [PubMed] [Google Scholar]
  14. Hunt D. F., Henderson R. A., Shabanowitz J., Sakaguchi K., Michel H., Sevilir N., Cox A. L., Appella E., Engelhard V. H. Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science. 1992 Mar 6;255(5049):1261–1263. doi: 10.1126/science.1546328. [DOI] [PubMed] [Google Scholar]
  15. Ioannides C. G., Fisk B., Fan D., Biddison W. E., Wharton J. T., O'Brian C. A. Cytotoxic T cells isolated from ovarian malignant ascites recognize a peptide derived from the HER-2/neu proto-oncogene. Cell Immunol. 1993 Oct 1;151(1):225–234. doi: 10.1006/cimm.1993.1233. [DOI] [PubMed] [Google Scholar]
  16. Ioannides C. G., Fisk B., Jerome K. R., Irimura T., Wharton J. T., Finn O. J. Cytotoxic T cells from ovarian malignant tumors can recognize polymorphic epithelial mucin core peptides. J Immunol. 1993 Oct 1;151(7):3693–3703. [PubMed] [Google Scholar]
  17. Ioannides C. G., Fisk B., Pollack M. S., Frazier M. L., Taylor Wharton J., Freedman R. S. Cytotoxic T-cell clones isolated from ovarian tumour infiltrating lymphocytes recognize common determinants on non-ovarian tumour clones. Scand J Immunol. 1993 Apr;37(4):413–424. doi: 10.1111/j.1365-3083.1993.tb03312.x. [DOI] [PubMed] [Google Scholar]
  18. Ioannides C. G., Freedman R. S., Platsoucas C. D., Rashed S., Kim Y. P. Cytotoxic T cell clones isolated from ovarian tumor-infiltrating lymphocytes recognize multiple antigenic epitopes on autologous tumor cells. J Immunol. 1991 Mar 1;146(5):1700–1707. [PubMed] [Google Scholar]
  19. Ioannides C. G., Ioannides M. G., O'Brian C. A. T-cell recognition of oncogene products: a new strategy for immunotherapy. Mol Carcinog. 1992;6(2):77–82. doi: 10.1002/mc.2940060202. [DOI] [PubMed] [Google Scholar]
  20. Kawakami Y., Eliyahu S., Delgado C. H., Robbins P. F., Sakaguchi K., Appella E., Yannelli J. R., Adema G. J., Miki T., Rosenberg S. A. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6458–6462. doi: 10.1073/pnas.91.14.6458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. King B. L., Carter D., Foellmer H. G., Kacinski B. M. Neu proto-oncogene amplification and expression in ovarian adenocarcinoma cell lines. Am J Pathol. 1992 Jan;140(1):23–31. [PMC free article] [PubMed] [Google Scholar]
  23. Kraus M. H., Popescu N. C., Amsbaugh S. C., King C. R. Overexpression of the EGF receptor-related proto-oncogene erbB-2 in human mammary tumor cell lines by different molecular mechanisms. EMBO J. 1987 Mar;6(3):605–610. doi: 10.1002/j.1460-2075.1987.tb04797.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Letessier E. M., Heo D. S., Okarma T., Johnson J. T., Herberman R. B., Whiteside T. L. Enrichment in tumor-reactive CD8+ T-lymphocytes by positive selection from the blood and lymph nodes of patients with head and neck cancer. Cancer Res. 1991 Aug 1;51(15):3891–3899. [PubMed] [Google Scholar]
  25. Madden D. R., Garboczi D. N., Wiley D. C. The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell. 1993 Nov 19;75(4):693–708. doi: 10.1016/0092-8674(93)90490-h. [DOI] [PubMed] [Google Scholar]
  26. Niehans G. A., Singleton T. P., Dykoski D., Kiang D. T. Stability of HER-2/neu expression over time and at multiple metastatic sites. J Natl Cancer Inst. 1993 Aug 4;85(15):1230–1235. doi: 10.1093/jnci/85.15.1230. [DOI] [PubMed] [Google Scholar]
  27. Rilke F., Colnaghi M. I., Cascinelli N., Andreola S., Baldini M. T., Bufalino R., Della Porta G., Ménard S., Pierotti M. A., Testori A. Prognostic significance of HER-2/neu expression in breast cancer and its relationship to other prognostic factors. Int J Cancer. 1991 Aug 19;49(1):44–49. doi: 10.1002/ijc.2910490109. [DOI] [PubMed] [Google Scholar]
  28. Ruppert J., Sidney J., Celis E., Kubo R. T., Grey H. M., Sette A. Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell. 1993 Sep 10;74(5):929–937. doi: 10.1016/0092-8674(93)90472-3. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Yoshino I., Goedegebuure P. S., Peoples G. E., Parikh A. S., DiMaio J. M., Lyerly H. K., Gazdar A. F., Eberlein T. J. HER2/neu-derived peptides are shared antigens among human non-small cell lung cancer and ovarian cancer. Cancer Res. 1994 Jul 1;54(13):3387–3390. [PubMed] [Google Scholar]
  31. 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]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES