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Characterization of HLA-A3-restricted Cytotoxic T Lymphocytes Reactive against the Widely Expressed Tumor Antigen Telomerase¹

Department of Adult Oncology, Dana-Farber Cancer Institute, and Departments of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115 [R. H. V., K. S. A., W. C. H., M. O. B., J. L. S., L. M. N.], and the Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142 [W. C. H.]

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.

Conclusion: 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.

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