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Dendritic cells reconstituted with human telomerase gene induce potent cytotoxic T-cell response against different types of tumors

Cancer Gene Therapy volume 10, pages 239–249 (2003)Cite this article

Abstract

Human telomerase reverse transcriptase (hTERT) is the catalytic component of a functional telomerase complex, which is important in maintaining cell immortality. In most normal human adult cells, the expression of telomerase is very low and/or transient. In contrast, almost 90% of human tumors express a relatively high level of telomerase implying the possibility of using hTERT as a universal candidate tumor antigen. In this study, we show that human monocyte-derived dendritic cells (DCs) lack telomerase activity. Similar to other normal somatic cells, DCs express the RNA (hTR) component but not the catalytic component, hTERT. We also show that telomerase activity could be reconstituted using either lipid-mediated transfection of the hTERT plasmid DNA or transduction with an E1-, E3-deleted adenoviral vector containing the hTERT gene. However, relative to plasmid transfection, adenoviral gene transfer produced higher levels of hTERT expression. Nine of 10 AdhTERT-transduced DCs were able to generate CTL responses, while only three of nine plasmid-transfected DCs did. CTLs primed against hTERT exhibited killing of telomerase positive but not telomerase negative tumor lines of diverse tissue origins. Antigenic specificity of these T cells to telomerase was further determined by introducing hTERT gene into a telomerase negative cell line, U2OS, by adenoviral transduction. Although some antigenic specificity was directed against adenoviral epitopes, the majority of CTLs were targeted against telomerase-derived antigen(s). Thus, the hTERT gene, particularly as delivered via the recombinant adenovirus, may be useful as vaccine to induce specific T-cell-mediated tumor immunity in cancer patients. In addition, our results suggest that telomerase activity and/or telomerase expression after hTERT gene transfer have a predictive value in the success of hTERT/DC-based cancer vaccination.

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Acknowledgements

We thank Lisa Cardoza for constructing the AdhTERT virus used in this study and Brian Murphy and Sharon Wang for providing excellent technical assistance. We also thank Drs Cal Harley and Iris Ferber for the critical reading of the manuscript.

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Author notes

  1. Maria Frolkis and Melissa B Fischer: MF and MBF contributed equally to this study.

Authors and Affiliations

  1. Department of Cell Biology, Geron Corporation, 230 Constitution Drive, Menlo Park, 94025, California, USA

    Maria Frolkis, Melissa B Fischer, Zhuo Wang, Jane S Lebkowski, Choy-Pik Chiu & Anish S Majumdar

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  1. Maria Frolkis
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Correspondence to Anish S Majumdar.

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Frolkis, M., Fischer, M., Wang, Z. et al. Dendritic cells reconstituted with human telomerase gene induce potent cytotoxic T-cell response against different types of tumors. Cancer Gene Ther 10, 239–249 (2003). https://doi.org/10.1038/sj.cgt.7700563

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