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Enhanced Induction of Telomerase-specific CD4⁺ T Cells Using Dendritic Cells Transfected with RNA Encoding a Chimeric Gene Product¹

Cancer Immunotherapy Program, Division of Urology, Department of Surgery [Z. S., J. V., A. Z. W., P. D., D. Y., V. T., J. H., J. D.], and Center for Cellular and Genetic Therapies, Department of Surgery [D. B., E. G.], Duke University Medical Center, Durham, North Carolina 27710

Dendritic cells (DCs) transfected with mRNA encoding human telomerase reverse transcriptase (hTERT) have been shown to represent potent inducers of CTLs and antitumor immunity. However, it has become widely accepted that not only CTLs but also CD4⁺ T helper cells are critical to the generation, as well as to the maintenance, of potent antitumor responses in vivo. In this study, we sought to determine whether human DCs transfected with mRNA encoding a chimeric hTERT/lysosome-associated membrane protein (LAMP-1) protein, carrying the endosomal/lysosomal sorting signal of the LAMP-1, are capable of stimulating concomitant hTERT-specific CD8⁺ and CD4⁺ T-cell responses in vitro. We show that processing of hTERT/LAMP-1 transcripts leads to enhanced stimulation of hTERT-specific CD4⁺ T cells and does not negatively affect intracellular generation and subsequent presentation of MHC class I epitopes, hence, generating a CTL response. These findings provide a preclinical rationale of using DCs transfected with the chimeric hTERT/LAMP-1 RNA in vaccine trials to facilitate generation of antigen-specific CD4⁺ T-cell responses that may be required to stimulate and maintain an optimal CD8⁺ CTL response in vivo.

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