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Human Telomerase Reverse Transcriptase-Specific T-Helper Responses Induced by Promiscuous Major Histocompatibility Complex Class II-Restricted Epitopes

Center for Cell and Gene Therapy [R. S., L. S., L. R., C. M. R., X. F. H., S-Y. C.] and Departments of Molecular and Human Genetics [R. S., L. S., L. R., S-Y. C.], Pediatrics [C. M. R., X. F. H.], and Urology [K. S.], Baylor College of Medicine, Houston, Texas 77030, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305 [G. S.]

ABSTRACT

An effective tumor vaccine may require the induction of both CTL and T-helper (Th) cell responses against tumor-associated antigens. Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of cancer cells and thus is a potential target for tumor vaccines. We therefore sought to identify promiscuous Th epitopes in hTERT, which can be presented by more than one MHC class II allele. Each of 10 peptides derived from hTERT that were predicted to bind to MHC class II molecules was found to be able to induce primary human T-cell responses in vitro. We then established CD4⁺ T-cell clones specific for these peptides and found that only hTERT₇₆₆ (LTDLQPYMRQFVAHL)-specific CD4⁺ Th cells were effective in recognizing naturally processed hTERT antigen. We further found that the naturally processed epitopes hTERT₇₆₆ and hTERT₆₇₂ (which was identified previously) were promiscuous and capable of inducing CD4⁺ T-cell responses in the context of several commonly found HLA-DR alleles, including DR1, DR7, and DR15 for hTERT₆₇₂, and DR4, DR11, and DR15 for hTERT₇₆₆. We further demonstrated that immunization of humanized HLA-DR4 transgenic mice with hTERT₇₆₆ peptide elicited antigen-specific Th responses that can recognize the antigenic peptides derived from hTERT protein and various hTERT-positive tumors, such as breast cancer, melanoma, and leukemia. It was also shown that T-cell precursors specific for the naturally processed epitopes are part of the T-cell repertoires in healthy donors and prostate cancer patients. Thus, these promiscuous, naturally processed Th epitopes in hTERT could be used to develop improved cancer vaccines through the simultaneous stimulation of CTL and Th cells against a broad spectrum of hTERT-positive tumors.

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