Characterization of HLA-A3-restricted cytotoxic T lymphocytes reactive against the widely expressed tumor antigen telomerase.
OBJECTIVE
We have reported previously that the telomerase catalytic subunit, human telomerase reverse transcriptase (hTERT), is a widely expressed tumor-associated antigen recognized by CTLs. A nine-amino acid peptide derived from hTERT binds strongly to HLA-A2 antigen and elicits CTL responses against a broad panel of hTERT+ tumors (but not hTERT+ hematopoietic progenitor cells). The applicability of hTERT as a potential target for anticancer immunotherapy would be widened by the identification of epitopes restricted to other common HLA alleles, such as HLA-A3 antigen.


METHODS
Using a method of epitope deduction, HLA-A3-restricted peptide epitopes were screened from hTERT and tested for immunogenicity in a human in vitro T-cell system.


RESULTS
The hTERT peptide K973 was used to generate specific CD8+ CTLs from HLA-A3+ cancer patients and healthy individuals. These CTLs lysed hTERT+ tumors from multiple histologies in an MHC-restricted fashion, suggesting that the epitope is naturally processed and presented by tumors. In contrast, highly enriched HLA-A3+ CD34+ peripheral blood progenitor cells or activated T cells were not lysed.


CONCLUSIONS
Given the expression of HLA-A2 and HLA-A3 antigen in the general population, these findings extend the potential applicability of hTERT as a therapeutic target to >60% of all cancer patients. The characterization of hTERT as a polyepitope, polyallelic tumor-associated antigen may provide an approach for circumventing therapy-induced resistance potentially mediated by antigenic- and allelic-loss tumor escape mutants.
Vonderheide
R H
RH
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. rhv@mail.med.upenn.edu
Anderson
K S
KS
Hahn
W C
WC
Butler
M O
MO
Schultze
J L
JL
Nadler
L M
LM
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology; D019013:CD40 Antigens / Q000032:analysis; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins; D000939:Epitopes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015791:HLA-A3 Antigen / Q000276:immunology* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019098:Telomerase / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D000939:Epitopes; D015791:HLA-A3 Antigen; D019098:Telomerase