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Identification of HLA DR7-restricted Epitopes from Human Telomerase Reverse Transcriptase Recognized by CD4+ T-Helper Cells¹

Center for Cell and Gene Therapy [R. S., X. F. H., S-Y. C.], and Departments of Molecular and Human Genetics [R. S., S-Y. C.], Pediatrics [X. F. H.], and Neurology [J. Z.], Baylor College of Medicine, Houston, Texas 77030, and Vaccinome, Kearny, New Jersey 07032 [J. H.]

CD4+ T cells play critical roles in initiating, regulating, and maintaining antitumor immuneresponses. One way to improve current tumor vaccines that mainly induce CTLs would be to activate antigen-specific CD4+ T cells that recognize MHC class II restricted tumor associated antigens. Human telomerase reverse transcriptase (hTRT) is preferentially expressed by various tumors and, therefore, could be a universal tumor antigen. In this study, we used a combined approach of using the prediction software TEPITOPE to select class II epitope candidates and in vitro T-cell biological analysis to identify class II-restricted epitope(s) in hTRT. We first identified several HLA-DR7-restricted class-II epitope candidates in hTRT by examining human T-cell responses to synthetic peptides. We then characterized these HLA-DR7-restricted hTRT epitope candidates by establishing and analyzing peptide-specific T-cell clones. It was demonstrated that CD4+ T cells specific for the HLA-DR7-restricted hTRT₆₇₂ epitope (RPGLLGASVLGLDDI) can respond to naturally processed hTRT proteins. Furthermore, the hTRT₆₇₂-specific T cells recognized hTRT antigen from various tumors, including prostate cancer, breast cancer, melanoma, and leukemia. Thus, the identification of the naturally processed HLA-DR7-restricted hTRT epitope, together with the previous finding of class I-restricted hTRT epitopes, provide a basis for the combined application of class I- and II-restricted hTRT epitopes to induce potent, long-term CD4+ and CD8+ T-cell responses against a broad spectrum of tumors.

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