Identification of a potential human telomerase reverse transcriptase-derived, HLA-A1-restricted cytotoxic T-lymphocyte epitope.
The catalytic subunit of human telomerase reverse transcriptase (hTERT) is expressed in the majority of tumor cells of different histological origins as opposed to most normal somatic cells. This implicates hTERT as a widely expressed tumor-associated antigen and an attractive candidate for antigen-specific tumor immunotherapy. T lymphocytes specific for hTERT-derived epitopes have been isolated and shown reactive with hTERT-expressing tumor cells. To further increase the applicability of hTERT as a target antigen for immunotherapy, we set out to identify potential hTERT-derived, HLA-A1-restricted cytotoxic T-lymphocyte (CTL) epitopes. The "reverse immunology" approach, involving computer-assisted epitope prediction, in vitro CTL induction, and tetramer-guided CTL isolation, resulted in specific CTLs against hTERT-derived, HLA-A1-binding peptides. Intermediate- to low-avidity CTLs were induced against the hTERT325-333 peptide and recognized endogenously processed hTERT. Recognition of endogenous hTERT depended on an increase of hTERT expression above normal levels in tumor cells through hTERT transduction, most probably as a result of limited CTL avidity. The altered peptide ligand hTERT699T-707 was designed to increase HLA-A1-binding affinity of the hTERT699-707 peptide and was used to induce CTLs. However, these CTLs poorly cross-recognized native hTERT699-707 and failed to recognize endogenously processed hTERT. In conclusion, our study has identified the hTERT325-333 peptide as a potential hTERT-derived epitope that may prove useful for induction and monitoring of hTERT-specific, HLA-A1-restricted CTL responses.
Schreurs
Marco W J
MW
Department of Pathology, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Kueter
Esther W M
EW
Scholten
Kirsten B J
KB
Kramer
Duco
D
Meijer
Chris J L M
CJ
Hooijberg
Erik
E
D000951:Antigens, Neoplasm / Q000276:immunology*; D004268:DNA-Binding Proteins; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015788:HLA-A1 Antigen / Q000276:immunology*; D006801:Humans; D008545:Melanoma / Q000276:immunology*; D010446:Peptide Fragments; D012878:Skin Neoplasms / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019098:Telomerase / Q000737:chemistry / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000939:Epitopes; D015788:HLA-A1 Antigen; D010446:Peptide Fragments; D019098:Telomerase
Blood. 2001 May 1;97(9):2903-7
11313288
Cancer Gene Ther. 2003 Mar;10(3):239-49
12637945
Immunogenetics. 1994;40(3):238-41
8039832
Nat Med. 2000 Sep;6(9):1011-7
10973321
J Immunol. 2002 Jun 1;168(11):5900-6
12023395
Cancer Immun. 2002 Oct 14;2:14
12747759
Immunogenetics. 1999 Nov;50(3-4):213-9
10602881
J Clin Invest. 2004 Feb;113(3):425-33
14755339
Oncogene. 2002 Jan 21;21(4):541-52
11850779
Eur J Immunol. 2001 Sep;31(9):2642-51
11536162
Oncogene. 2002 Jan 21;21(4):674-9
11850795
J Immunol. 2000 Oct 15;165(8):4239-45
11035057
Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4102-7
8633023
Cell Immunol. 1999 Jul 10;195(1):10-7
10433792
Int J Cancer. 2004 Feb 10;108(4):571-9
14696122
Hum Immunol. 2003 Feb;64(2):245-55
12559627
J Immunol. 1994 Apr 15;152(8):3913-24
8144960
Cancer Res. 2003 May 1;63(9):2127-33
12727829
Science. 1994 Dec 23;266(5193):2011-5
7605428
Int Rev Immunol. 2003 Mar-Apr;22(2):81-112
12962271
J Immunol. 1998 Dec 15;161(12):6956-62
9862730
J Immunol Methods. 1996 Sep 27;196(2):137-51
8841452
Clin Cancer Res. 2004 Jul 15;10(14):4688-98
15269141
Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14578-83
11121060
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12275-80
12218171
Clin Cancer Res. 2003 Oct 15;9(13):4743-55
14581345
Clin Cancer Res. 2001 Nov;7(11):3343-8
11705846
J Immunother. 2002 Sep-Oct;25(5):429-38
12218781
Clin Cancer Res. 2004 Feb 1;10(3):828-39
14871958
Immunity. 1999 Jun;10(6):673-9
10403642
Hum Genet. 1986 Aug;73(4):320-6
3017841
J Immunol. 2003 Sep 15;171(6):2912-21
12960314
Immunol Today. 1999 Apr;20(4):177-80
10203715
Trends Cell Biol. 2003 Jun;13(6):289-94
12791294
Nat Immunol. 2001 Aug;2(8):711-7
11477407
J Immunol Methods. 1984 Aug 3;72(1):219-27
6086760
Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4796-801
10759561
J Immunol. 2000 Dec 1;165(11):6644-52
11086110