Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells.
Telomerase reverse transcriptase (TRT) is a tumor-associated antigen expressed in the vast majority of human tumors and is presently one of the most promising target candidates for a therapeutic cancer vaccine. TRT is also expressed at low level in selected tissues and should be considered a self antigen. In the present study we sought to develop cytotoxic T lymphocytes (CTL) responses directed against human (h)TRT peptides with low relative affinity for which the available repertoire is to be preferentially spared from tolerance. This was accomplished by using analogue peptides of hTRT whose relative affinity for the MHC was increased by a targeted (-->Tyr) substitution in position one. By immunizing HLA A2.1 transgenic mice with these analogue peptides, we identified one such low relative affinity peptide (p572) that is endogenously processed and presented by HLA A2.1 in tumor cells, and is recognized by specific CTL. We used the highly immunogenic analogue peptide to successfully induce TRT-specific CTL in cancer patients and normal donors. CTL against p572-lysed human and mouse tumor cells but not activated autologous B cells. This peptide represents, therefore, an important candidate component of a cancer vaccine based on a TRT substrate and validates the strategy of targeting peptides with low affinity for the MHC for cancer immunotherapy.
Hernandez
Javier
J
Department of Medicine and Cancer Center, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0837, USA.
Garcia-Pons
Francisco
F
Lone
Yu Chun
YC
Firat
Huseyin
H
Schmidt
Joseph D
JD
Langlade-Demoyen
Pierre
P
Zanetti
Maurizio
M
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology; D001665:Binding Sites; D019496:Cancer Vaccines / Q000235:genetics / Q000494:pharmacology; D003429:Cross Reactions; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004268:DNA-Binding Proteins; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology*; D019098:Telomerase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000090324:Tumor Protein, Translationally-Controlled 1
D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; D019098:Telomerase