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 tumo r-associated antigen recognized by CTLs. A nine-amino acid peptide derived from hTERT binds strongly to HLA-A2 antigen and elicits CTL responses again st a broad panel of hTERT(+) tumors (but not hTERT(+) hematopoietic progeni tor cells). The applicability of hTERT as a potential target for anticancer immunotherapy would be widened by the identification of epitopes restricte d 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 f rom HLA-A3(+) cancer patients and healthy individuals. These CTLs lysed hTE RT(+) tumors from multiple histologies in an MHC-restricted fashion, sugges ting that the epitope is naturally processed and presented by tumors. In co ntrast, highly enriched HLA-A3(+) CD34(+) peripheral blood progenitor cells or activated T cells were not lysed. Conclusion: Given the expression of HLA-A2 and HLA-A3 antigen in the genera l population, these findings extend the potential applicability of hTERT as a therapeutic target to > 60 % of all cancer patients. The characterizatio n of hTERT as a polyepitope, polyallelic tumor-associated antigen may provi de an approach for circumventing therapy-induced resistance potentially med iated by antigenic- and allelic-loss tumor escape mutants.