The HLA A*0201-restricted hTERT540-548 peptide is not detected on tumor cells by a CTL clone or a high-affinity T-cell receptor

被引:38
作者
Purbhoo, Marco A.
Li, Yi
Sutton, Deborah H.
Brewer, Joanna E.
Gostick, Emma
Bossi, Giovanna
Laugel, Bruno
Moysey, Ruth
Baston, Emma
Liddy, Nathaniel
Cameron, Brian
Bennett, Alan D.
Ashfield, Rebecca
Milicic, Anita
Price, David A.
Classon, Brendan J.
Sewell, Andrew K.
Jakobsen, Bent K.
机构
[1] Avidex Ltd, Abingdon OX14 4RX, Oxon, England
[2] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Med, Oxford OX3 9DU, England
基金
英国医学研究理事会;
关键词
D O I
10.1158/1535-7163.MCT-07-0092
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Tumor-associated human telomerase reverse transcriptase [hTERT) is expressed in > 85% of human tumors but not in most normal cells. As a result, this antigen has received considerable attention from those interested in cancer immunotherapy. Specifically, there has been strong interest in MHC class I-associated peptides derived from hTERT because these are expressed on the cell surface and thus may enable the targeting of tumor cells. Much of this interest has focused on peptide 540-548, ILAKFLHWL, which was predicted to exhibit the strongest binding to the common HLA A*0201 presenting molecule. The hTERT(540-548) peptide is currently being assessed in therapeutic vaccination trials; however, there is controversy surrounding whether it is naturally processed and presented on the surface of neoplastic cells. Here, we generate two highly sensitive reagents to assess the presentation of hTERT(540-548) on tumor cells: (a) a CD8(+) CTL clone, and (b) a recombinant T-cell receptor (TCR) that binds with picomolar affinity and a half-life exceeding 14 h. This TCR enables the identification of individual HLA A2-hTERT(540-548) complexes on the cell surface. The use of both this TCR and the highly antigen-sensitive CTL clone shows that the hTERT(540-548) peptide cannot be detected on the surface of tumor cells, indicating that this peptide is not a naturally presented epitope. We propose that, in future, rigorous methods must be applied for the validation of peptide epitopes used for clinical applications.
引用
收藏
页码:2081 / 2091
页数:11
相关论文
共 47 条
[1]   Regulators of apoptosis: Suitable targets for immune therapy of cancer [J].
Andersen, MH ;
Becker, JC ;
Straten, PT .
NATURE REVIEWS DRUG DISCOVERY, 2005, 4 (05) :399-409
[2]  
Ayyoub M, 2001, EUR J IMMUNOL, V31, P2642, DOI 10.1002/1521-4141(200109)31:9<2642::AID-IMMU2642>3.0.CO
[3]  
2-6
[4]   Stable, soluble T-cell receptor molecules for crystallization and therapeutics [J].
Boulter, JM ;
Glick, M ;
Todorov, PT ;
Baston, E ;
Sami, M ;
Rizkallah, P ;
Jakobsen, BK .
PROTEIN ENGINEERING, 2003, 16 (09) :707-711
[5]   Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer [J].
Brunsvig, Paal F. ;
Aamdal, Steinar ;
Gjertsen, Marianne K. ;
Kvalheim, Gunnar ;
Markowski-Grimsrud, Carrie J. ;
Sve, Ingunn ;
Dyrhaug, Marianne ;
Trachsel, Sissel ;
Moller, Mona ;
Eriksen, Jon A. ;
Gaudernack, Gustav .
CANCER IMMUNOLOGY IMMUNOTHERAPY, 2006, 55 (12) :1553-1564
[6]   Telomeres, telomerase, and myc.: An update [J].
Cerni, C .
MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH, 2000, 462 (01) :31-47
[7]   Identification of NY-ESO-1 peptide analogues capable of improved stimulation of tumor-reactive CTL [J].
Chen, JL ;
Dunbar, PR ;
Gileadi, U ;
Jäger, E ;
Gnjatic, S ;
Nagata, Y ;
Stockert, E ;
Panicalli, DL ;
Chen, YT ;
Knuth, A ;
Old, LJ ;
Cerundolo, V .
JOURNAL OF IMMUNOLOGY, 2000, 165 (02) :948-955
[8]   Selective targeting of melanoma and APCs using a recombinant antibody with TCR-like specificity directed toward a melanoma differentiation antigen [J].
Denkberg, G ;
Lev, A ;
Eisenbach, L ;
Benhar, I ;
Reiter, Y .
JOURNAL OF IMMUNOLOGY, 2003, 171 (05) :2197-2207
[9]   Artificial antigen-presenting cells transduced with telomerase efficiently expand epitope-specific, human leukocyte antigen-restricted cytotoxic T cells [J].
Dupont, J ;
Latouche, JB ;
Ma, C ;
Sadelain, N .
CANCER RESEARCH, 2005, 65 (12) :5417-5427
[10]   Frequency of telomerase-specific CD8+ T lymphocytes in patients with cancer [J].
Filaci, G ;
Fravega, M ;
Setti, M ;
Traverso, P ;
Millo, E ;
Fenoglio, D ;
Negrini, S ;
Ferrera, F ;
Romagnoli, A ;
Basso, M ;
Contini, P ;
Rizzi, M ;
Ghio, M ;
Benatti, U ;
Damonte, G ;
Ravetti, JL ;
Carmignani, G ;
Zanetti, M ;
Indiveri, F .
BLOOD, 2006, 107 (04) :1505-1512