Immunogenic HLA-B*0702-restricted epitopes derived from human telomerase reverse transcriptase that elicit antitumor cytotoxic T-cell responses.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

• Authors: Olivier Adotévi, Karine Mollier, Christine Neuveut, Sylvain Cardinaud, Emmanuelle Boulanger, Blandine Mignen, Wolf-Hervé Fridman, Maurizio Zanetti, Pierre Charneau, Eric Tartour, François Lemonnier, Pierre Langlade-Demoyen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 10 Pg. 3158-67 (May 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16707616 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cancer Vaccines
• DNA-Binding Proteins
• Epitopes, T-Lymphocyte
• HLA-B Antigens
• HLA-B*07:02 antigen
• HLA-B7 Antigen
• Peptide Fragments
• Vaccines, Synthetic
• DNA
• Telomerase

Topics

• Animals
• Cancer Vaccines (immunology)
• Cell Line
• DNA
• DNA-Binding Proteins (metabolism)
• Epitopes, T-Lymphocyte (immunology)
• HLA-B Antigens (genetics, immunology)
• HLA-B7 Antigen
• Humans
• Immunotherapy (methods)
• Mice
• Mice, Transgenic
• Neoplasms (immunology, therapy)
• Peptide Fragments
• Plasmids
• Telomerase (metabolism)
• Vaccination
• Vaccines, Synthetic (immunology)