Immunogenic HLA-B*0702-restricted epitopes derived from human telomerase reverse transcriptase that elicit antitumor cytotoxic T-cell responses.
OBJECTIVE
The human telomerase reverse transcriptase (hTERT) is considered as a potential target for cancer immunotherapy because it is preferentially expressed in tumor cells. To increase the applicability of hTERT-based immunotherapy, we set out to identify CTL epitopes in hTERT restricted by HLA-B*0702 molecule, a common MHC class I allele.


METHODS
HLA-B*0702-restricted peptides from hTERT were selected by using a method of epitope prediction and tested for their immunogenicity in human (in vitro) and HLA-B*0702 transgenic mice (in vivo).


RESULTS
All the six hTERT peptides that were predicted to bind to HLA-B*0702 molecule were found to induce primary human CTL responses in vitro. The peptide-specific CD8+ CTL lines were tested against various hTERT+ tumor cells. Although differences were observed according to the tumor origin, only three CTL lines specific for p277, p342, and p351 peptides exhibited cytotoxicity against tumor cells in a HLA-B*0702-restricted manner. In addition, this cytotoxicity was inhibited by the addition of peptide-loaded cold target cells and indicated that these epitopes are naturally processed and presented on the tumor cells. Further, in vivo studies using humanized HLA-B*0702 transgenic mice showed that all the candidate peptides were able to induce CTL responses after peptide immunization. Furthermore, vaccination with a plasmid DNA encoding full-length hTERT elicited peptide-specific CTL responses, indicating that these epitopes are efficiently processed in vivo.


CONCLUSIONS
Together with previously reported hTERT epitopes, the identification of new CTL epitopes presented by HLA-B*0702 increases the applicability of hTERT-based immunotherapy to treating cancer.
Adotévi
Olivier
O
Institut National de la Sante et de la Recherche Medicale U255, Université René Descartes, Unité d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Assistance-Public Hôpitaux de Paris, France. Olivier.adotevi@hop.egp.ap-hop-paris.fr
Mollier
Karine
K
Neuveut
Christine
C
Cardinaud
Sylvain
S
Boulanger
Emmanuelle
E
Mignen
Blandine
B
Fridman
Wolf-Hervé
WH
Zanetti
Maurizio
M
Charneau
Pierre
P
Tartour
Eric
E
Lemonnier
François
F
Langlade-Demoyen
Pierre
P
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology; D002460:Cell Line; D004247:DNA; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D015793:HLA-B7 Antigen; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D010446:Peptide Fragments; D010957:Plasmids; D019098:Telomerase / Q000378:metabolism*; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000276:immunology
D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; C477444:HLA-B*07:02 antigen; D015793:HLA-B7 Antigen; D010446:Peptide Fragments; D014614:Vaccines, Synthetic; D004247:DNA; D019098:Telomerase