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‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

Abstract

T-cell priming is strongly affected by the longevity of antigen-bearing dendritic cells (DCs), which are typically short-lived in lymphoid tissues. ‘Survival gene’ Bcl-xl is critical for the lifespan of DCs in vivo. Here, we showed that in vivo coadministration of Bcl-xl under control of the DC-specific promoter (CD11c-Bcl-xl) and TRP2hsp70 DNA prolonged T-cell stimulation by DCs and augmented TRP2-specific-IFN-γ-producing CD8+ T-cell responses. Consistent with these findings, enhanced protection and significant therapeutic immunity to B16 melanoma was generated by this coimmunization strategy, which also augmented therapeutic immunity to GL-26 tumor. In this B16 melanoma model, results from animal experiments with depletion of immune cells indicate that CD8+ T cells and NK cells are important in the antitumor immunity induced by this coimmunization strategy. These observations suggest that ‘survival gene’ Bcl-xl potentiates the magnitude of antigen-specific-CD8+ T-cell responses and the efficacy of antitumor immunity induced by DNA vaccine, and is relevant for the design of in vivo targeted DC-based vaccine strategies to improve immunity against cancer.

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Acknowledgements

We are indebted to T Brocker (Ludwig-Maximilians-Universitat Munchen) for the CD11c promoter, X Ying (University of Pittsburgh) for the human Bcl-xl cDNA, J Yang (NCI) for the murine TRP2 cDNA, R Morimoto (Northwestern University) for the human hsp70 cDNA, R Prins and L Liau (UCLA) for the GL-26 cell line, H Waldmann (University of Oxford) for the purified anti-CD4 and anti-CD8 antibodies, J Kirkwood and W Storkus (University of Pittsburgh) and members of Falo's laboratory for valuable discussion, and Experimental Animal Facility technicians for animal care. This work was supported by a start-up fund from Department of Dermatology of The University of Pittsburgh (ZY) and by grants from the NIAMS and NIAID (LDF). We thank T-C Wu (The Johns Hopkins Medical Institutions) for critical review of this manuscript.

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Kim, J., Chen, J., Majumder, N. et al. ‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity. Gene Ther 12, 1517–1525 (2005). https://doi.org/10.1038/sj.gt.3302584

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