Abstract
Retinoblastoma binding protein 1 (RBP-1) is a 143-kDa nuclear phosphoprotein that promotes cell growth by inhibiting the product of retinoblastoma tumour suppressor gene (pRB). We recently found that RBP-1 contains KASIFLK, a heptameric peptide (250–256) recognized by human antibodies and overexpressed by breast cancer cells. In the present study, we demonstrate that human T-cells stimulated with RBP-1 decameric peptides containing KASIFLK can kill human breast cancer cells. These decamers, GLQKASIFLK (247–256) and KASIFLKTRV (250–259), have anchor motifs for both HLA-A2 and HLA-A3. Peripheral blood lymphocytes from 41 normal donors were stimulated by these peptides in culture media containing 15 IU ml−1 interleukin-2, 25 IU ml−1 interleukin-7 and 500 IU ml−1 granulocyte–macrophage colony-stimulating factor. Cytotoxic activity of the T-cells was assessed against autologous B lymphoblastoid cells pulsed with each peptide. Stimulation by GLQKASIFLK generated specific cytotoxic T lymphocyte (CTL) lines from HLA-A2, A3 donors, HLA-A2 donors and HLA-A3 donors. Stimulation with KASIFLKTRV generated specific CTL lines from HLA-A2 donors. No HLA-A2−, A3− CTL line showed specific cytotoxicity against these target cells. These CTL lines were also cytotoxic against HLA-A2 and HLA-A3 breast cancer cells but not against normal fibroblastoid cell lines, normal epidermal cell lines, or a melanoma cell line. RBP-1 peptide antigens may be of clinical significance as a potential peptide vaccine against human breast cancer. © 1999 Cancer Research Campaign
Keywords: CTL, RBP-1, Rb protein, HLA, breast cancer, peptide
Full Text
The Full Text of this article is available as a PDF (150.6 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bookstein R., Shew J. Y., Chen P. L., Scully P., Lee W. H. Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene. Science. 1990 Feb 9;247(4943):712–715. doi: 10.1126/science.2300823. [DOI] [PubMed] [Google Scholar]
- Boon T., Cerottini J. C., Van den Eynde B., van der Bruggen P., Van Pel A. Tumor antigens recognized by T lymphocytes. Annu Rev Immunol. 1994;12:337–365. doi: 10.1146/annurev.iy.12.040194.002005. [DOI] [PubMed] [Google Scholar]
- Cao J., Gao T., Giuliano A. E., Irie R. F. Recognition of an epitope of a breast cancer antigen by human antibody. Breast Cancer Res Treat. 1999 Feb;53(3):279–290. doi: 10.1023/a:1006115922401. [DOI] [PubMed] [Google Scholar]
- Celis E., Fikes J., Wentworth P., Sidney J., Southwood S., Maewal A., Del Guercio M. F., Sette A., Livingston B. Identification of potential CTL epitopes of tumor-associated antigen MAGE-1 for five common HLA-A alleles. Mol Immunol. 1994 Dec;31(18):1423–1430. doi: 10.1016/0161-5890(94)90158-9. [DOI] [PubMed] [Google Scholar]
- 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]
- Defeo-Jones D., Huang P. S., Jones R. E., Haskell K. M., Vuocolo G. A., Hanobik M. G., Huber H. E., Oliff A. Cloning of cDNAs for cellular proteins that bind to the retinoblastoma gene product. Nature. 1991 Jul 18;352(6332):251–254. doi: 10.1038/352251a0. [DOI] [PubMed] [Google Scholar]
- Fattaey A. R., Helin K., Dembski M. S., Dyson N., Harlow E., Vuocolo G. A., Hanobik M. G., Haskell K. M., Oliff A., Defeo-Jones D. Characterization of the retinoblastoma binding proteins RBP1 and RBP2. Oncogene. 1993 Nov;8(11):3149–3156. [PubMed] [Google Scholar]
- Germain R. N. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell. 1994 Jan 28;76(2):287–299. doi: 10.1016/0092-8674(94)90336-0. [DOI] [PubMed] [Google Scholar]
- Gnjatic S., Bressac-de Paillerets B., Guillet J. G., Choppin J. Mapping and ranking of potential cytotoxic T epitopes in the p53 protein: effect of mutations and polymorphism on peptide binding to purified and refolded HLA molecules. Eur J Immunol. 1995 Jun;25(6):1638–1642. doi: 10.1002/eji.1830250625. [DOI] [PubMed] [Google Scholar]
- Heemels M. T., Ploegh H. Generation, translocation, and presentation of MHC class I-restricted peptides. Annu Rev Biochem. 1995;64:463–491. doi: 10.1146/annurev.bi.64.070195.002335. [DOI] [PubMed] [Google Scholar]
- Hoon D. S., Okamoto T., Wang H. J., Elashoff R., Nizze A. J., Foshag L. J., Gammon G., Morton D. L. Is the survival of melanoma patients receiving polyvalent melanoma cell vaccine linked to the human leukocyte antigen phenotype of patients? J Clin Oncol. 1998 Apr;16(4):1430–1437. doi: 10.1200/JCO.1998.16.4.1430. [DOI] [PubMed] [Google Scholar]
- Huang S., Lee W. H., Lee E. Y. A cellular protein that competes with SV40 T antigen for binding to the retinoblastoma gene product. Nature. 1991 Mar 14;350(6314):160–162. doi: 10.1038/350160a0. [DOI] [PubMed] [Google Scholar]
- Kaelin W. G., Jr, Krek W., Sellers W. R., DeCaprio J. A., Ajchenbaum F., Fuchs C. S., Chittenden T., Li Y., Farnham P. J., Blanar M. A. Expression cloning of a cDNA encoding a retinoblastoma-binding protein with E2F-like properties. Cell. 1992 Jul 24;70(2):351–364. doi: 10.1016/0092-8674(92)90108-o. [DOI] [PubMed] [Google Scholar]
- Kaelin W. G., Jr, Pallas D. C., DeCaprio J. A., Kaye F. J., Livingston D. M. Identification of cellular proteins that can interact specifically with the T/E1A-binding region of the retinoblastoma gene product. Cell. 1991 Feb 8;64(3):521–532. doi: 10.1016/0092-8674(91)90236-r. [DOI] [PubMed] [Google Scholar]
- 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]
- Lee E. Y., To H., Shew J. Y., Bookstein R., Scully P., Lee W. H. Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science. 1988 Jul 8;241(4862):218–221. doi: 10.1126/science.3388033. [DOI] [PubMed] [Google Scholar]
- Lee W. H., Bookstein R., Hong F., Young L. J., Shew J. Y., Lee E. Y. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science. 1987 Mar 13;235(4794):1394–1399. doi: 10.1126/science.3823889. [DOI] [PubMed] [Google Scholar]
- Morioka N., Kikumoto Y., Hoon D. S., Morton D. L., Irie R. F. A decapeptide (Gln-Asp-Leu-Thr-Met-Lys-Tyr-Gln-Ile-Phe) from human melanoma is recognized by CTL in melanoma patients. J Immunol. 1994 Dec 15;153(12):5650–5658. [PubMed] [Google Scholar]
- Nijman H. W., Van der Burg S. H., Vierboom M. P., Houbiers J. G., Kast W. M., Melief C. J. p53, a potential target for tumor-directed T cells. Immunol Lett. 1994 May;40(2):171–178. doi: 10.1016/0165-2478(94)90189-9. [DOI] [PubMed] [Google Scholar]
- Otterson G. A., Kratzke R. A., Lin A. Y., Johnston P. G., Kaye F. J. Alternative splicing of the RBP1 gene clusters in an internal exon that encodes potential phosphorylation sites. Oncogene. 1993 Apr;8(4):949–957. [PubMed] [Google Scholar]
- Peace D. J., Smith J. W., Chen W., You S. G., Cosand W. L., Blake J., Cheever M. A. Lysis of ras oncogene-transformed cells by specific cytotoxic T lymphocytes elicited by primary in vitro immunization with mutated ras peptide. J Exp Med. 1994 Feb 1;179(2):473–479. doi: 10.1084/jem.179.2.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Peoples G. E., Yoshino I., Douville C. C., Andrews J. V., Goedegebuure P. S., Eberlein T. J. TCR V beta 3+ and V beta 6+ CTL recognize tumor-associated antigens related to HER2/neu expression in HLA-A2+ ovarian cancers. J Immunol. 1994 May 15;152(10):4993–4999. [PubMed] [Google Scholar]
- Rammensee H. G., Friede T., Stevanoviíc S. MHC ligands and peptide motifs: first listing. Immunogenetics. 1995;41(4):178–228. doi: 10.1007/BF00172063. [DOI] [PubMed] [Google Scholar]
- Rivoltini L., Kawakami Y., Sakaguchi K., Southwood S., Sette A., Robbins P. F., Marincola F. M., Salgaller M. L., Yannelli J. R., Appella E. Induction of tumor-reactive CTL from peripheral blood and tumor-infiltrating lymphocytes of melanoma patients by in vitro stimulation with an immunodominant peptide of the human melanoma antigen MART-1. J Immunol. 1995 Mar 1;154(5):2257–2265. [PubMed] [Google Scholar]
- Sidney J., Grey H. M., Kubo R. T., Sette A. Practical, biochemical and evolutionary implications of the discovery of HLA class I supermotifs. Immunol Today. 1996 Jun;17(6):261–266. doi: 10.1016/0167-5699(96)80542-1. [DOI] [PubMed] [Google Scholar]
- Takahashi T., Irie R. F., Morton D. L., Hoon D. S. Recognition of gp43 tumor-associated antigen peptide by both HLA-A2 restricted CTL lines and antibodies from melanoma patients. Cell Immunol. 1997 Jun 15;178(2):162–171. doi: 10.1006/cimm.1997.1126. [DOI] [PubMed] [Google Scholar]
- Takahashi T., Irie R. F., Nishinaka Y., Hoon D. S. 707-AP peptide recognized by human antibody induces human leukocyte antigen A2-restricted cytotoxic T lymphocyte killing of melanoma. Clin Cancer Res. 1997 Aug;3(8):1363–1370. [PubMed] [Google Scholar]
- Traversari C., van der Bruggen P., Luescher I. F., Lurquin C., Chomez P., Van Pel A., De Plaen E., Amar-Costesec A., Boon T. 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. 1992 Nov 1;176(5):1453–1457. doi: 10.1084/jem.176.5.1453. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Van Elsas A., Nijman H. W., Van der Minne C. E., Mourer J. S., Kast W. M., Melief C. J., Schrier P. I. Induction and characterization of cytotoxic T-lymphocytes recognizing a mutated p21ras peptide presented by HLA-A*0201. Int J Cancer. 1995 May 4;61(3):389–396. doi: 10.1002/ijc.2910610319. [DOI] [PubMed] [Google Scholar]
- Wiman K. G. The retinoblastoma gene: role in cell cycle control and cell differentiation. FASEB J. 1993 Jul;7(10):841–845. doi: 10.1096/fasebj.7.10.8393817. [DOI] [PubMed] [Google Scholar]
