Characterization of HLA-A3-restricted cytotoxic T lymphocytes reactive against the widely expressed tumor antigen telomerase

Purpose: 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. Experimental Design: 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.