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Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells.

Abstract

The polypeptide component of telomerase (TERT) is an attractive candidate for a broadly expressed tumor rejection antigen because telomerase is silent in normal tissues but is reactivated in more than 85% of cancers. Here we show that immunization against TERT induces immunity against tumors of unrelated origin. Immunization of mice with TERT RNA-transfected dendritic cells (DC) stimulated cytotoxic T lymphocytes (CTL), which lysed melanoma and thymoma tumor cells and inhibited the growth of three unrelated tumors in mice of distinct genetic backgrounds. TERT RNA-transfected human DC stimulated TERT-specific CTL in vitro that lysed human tumor cells, including Epstein Barr virus (EBV)-transformed B cells as well as autologous tumor targets from patients with renal and prostate cancer. Tumor RNA-transfected DC were used as surrogate targets in the CTL assays, obviating the difficulties in obtaining tumor cells from cancer patients. In one instance, where a tumor cell line was successfully established in culture from a patient with renal cancer, the patient's tumor cells were efficiently lysed by the CTL. Immunization with tumor RNA was generally more effective than immunization with TERT RNA, suggesting that an optimal immunization protocol may have to include TERT as well as additional tumor antigens.

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Figure 1: TERT RNA-transfected DC induce CTL in mice that lyse unrelated tumor targets.
Figure 2: Immunization with dendritic cells transfected with TERT RNA engenders anti-tumor immunity in mice.
Figure 3: TERT-specific CTL lyse EBV-transformed B cells (BLCL) in vitro.
Figure 4: DC transfected with TERT RNA stimulated TERT-specific CTL capable of recognizing tumor targets from patients with renal cancer.
Figure 5: TERT-specific CTL were stimulated by DC transfected with TERT RNA.

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Acknowledgements

The authors wish to thank David Snyder for animal care, Doris Coleman for patient recruitment, Monica Fernandes-Casal and Kristin Keck for generation of murine DC, Alivelu Basara and XuRong Jiang for TERT RT-PCR studies and Judy Hall for technical assistance in the preparation of the manuscript. This study was supported by a generous anonymous gift to the Duke University Cancer Center.

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Correspondence to Eli Gilboa.

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Nair, S., Heiser, A., Boczkowski, D. et al. Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells. . Nat Med 6, 1011–1017 (2000). https://doi.org/10.1038/79519

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