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Human telomerase reverse transcriptase-specific T-helper responses induced by promiscuous major histocompatibility
Roland Schroers1, Lei Shen, Lisa Rollins
1Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
Summary
Identifying promiscuous T-helper epitopes in human telomerase reverse transcriptase (hTERT) can enhance cancer vaccines. These epitopes stimulate T-cell responses against hTERT-positive tumors, aiding both CTL and Th cell induction for broader efficacy.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- Effective tumor vaccines require both cytotoxic T-lymphocyte (CTL) and T-helper (Th) cell responses against tumor-associated antigens.
- Human telomerase reverse transcriptase (hTERT) is a promising cancer vaccine target due to its high expression in over 85% of cancer cells.
- Identifying promiscuous T-helper epitopes, which bind to multiple MHC class II alleles, is crucial for broad vaccine applicability.
Purpose of the Study:
- To identify promiscuous T-helper epitopes within human telomerase reverse transcriptase (hTERT).
- To evaluate the ability of these epitopes to induce T-cell responses and recognize naturally processed tumor antigens.
- To assess the potential of these epitopes for developing broadly effective cancer vaccines.
Main Methods:
- Peptides derived from hTERT were predicted to bind MHC class II molecules and tested for in vitro human T-cell responses.
- CD4(+) T-cell clones specific for hTERT peptides were established to assess recognition of naturally processed antigens.
- Promiscuous epitopes were identified by their ability to induce CD4(+) T-cell responses across various HLA-DR alleles.
- Immunization of humanized HLA-DR4 transgenic mice with hTERT(766) peptide was performed to evaluate in vivo T-cell responses.
Main Results:
- Ten hTERT-derived peptides induced primary human T-cell responses in vitro.
- hTERT(766)-specific CD4(+) T-helper cells effectively recognized naturally processed hTERT antigen.
- The naturally processed epitopes hTERT(766) and hTERT(672) were promiscuous, inducing CD4(+) T-cell responses with common HLA-DR alleles (DR1, DR4, DR7, DR11, DR15).
- Immunization with hTERT(766) peptide in mice elicited antigen-specific Th responses recognizing hTERT and various hTERT-positive tumors.
- T-cell precursors for these epitopes exist in healthy donors and prostate cancer patients.
Conclusions:
- Promiscuous, naturally processed T-helper epitopes in hTERT have been identified.
- These epitopes can stimulate T-cell responses in the context of common HLA-DR alleles and in vivo.
- These findings support the development of improved cancer vaccines targeting a broad spectrum of hTERT-positive tumors by simultaneously stimulating CTL and Th cells.