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Effective induction of antiglioma cytotoxic T cells by coadministration of interferon-β gene vector and dendritic cells

Cancer Gene Therapy volume 10, pages 549–558 (2003)Cite this article

Abstract

As type I interferons (IFNs) enhance the stimulatory activity of dendritic cells (DCs), we hypothesized that transfection of glioma cells with the IFN-β gene in the presence of DCs would provide particularly effective antitumor activity by both facilitating apoptosis of glioma cells and presenting the resulting glioma antigens to T cell by DCs, thereby inducing specific T-cell responses against glioma cells. A mouse glioma cell line 203G was first transfected with cDNA encoding IFN-β using cationic liposomes, then cocultured with syngeneic bone marrow-derived DCs and naïve splenic T cells. The 203G cells were almost completely killed following 96-hour coculture with DCs and T cells, and strong tumor-specific cytotoxic T-lymphocyte (CTL) activity accompanied by high level interleukin (IL)-12 and IFN-γ production was observed in culture. In addition, omission of either IFN-β gene delivery, DCs or T cells from the coculture completely abrogated the induction of the CTL activity, suggesting that the combination of these components was required to elicit an optimal effect. On the basis of these in vitro data, syngeneic animals bearing subcutaneous 203G tumors received intratumoral injections of IFN-β gene and DCs. Suppression of the tumor growth by this combinational therapy was superior to treatment with DC or IFN-β gene solely. This combination may constitute a new therapeutic strategy to induce potent antiglioma immune responses.

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Abbreviations

IFN:

interferon

DC:

dendritic cell

CTL:

cytotoxic T cell

IL:

interleukin

TNF:

tumor necrosis factor

NK:

natural killer

TRAIL:

tumor necrosis factor-a (TNF-a)-related apoptosis-inducing ligand

Neo-R:

neomycin resistant gene

VEC-DIC:

video-enhanced contrast-differential contrast

CM:

complete media

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Acknowledgements

We thank Drs William H Chambers, Andrea Gambotto and Paul Robbins (University of Pittsburgh) for their helpful suggestions and discussions. We also thank Toray Industry Co. for providing recombinant mouse IFN-β. This work was supported by NIH R01 NS37704, NIH/NINDS (1P01 NS40923) and a Copeland Foundation Grant from Pittsburgh Foundation.

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Authors and Affiliations

  1. Department of Bio-Medicine, Nagoya University School of Medicine, Nagoya, Japan

    Norimoto Nakahara

  2. Department of Neurological Surgery, University of Pittsburgh, Cancer Institute, Pittsburgh, Pennsylvania, USA

    Ian F Pollack & Hideho Okada

  3. Department of Surgery, University of Pittsburgh, Cancer Institute, Pittsburgh, Pennsylvania, USA

    Walter J Storkus & Hideho Okada

  4. Department of Neurosurgery, Nagoya Graduate School of Medicine, Nagoya, Japan

    Toshihiko Wakabayashi & Jun Yoshida

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  1. Norimoto Nakahara
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  2. Ian F Pollack
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Correspondence to Hideho Okada.

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Nakahara, N., Pollack, I., Storkus, W. et al. Effective induction of antiglioma cytotoxic T cells by coadministration of interferon-β gene vector and dendritic cells. Cancer Gene Ther 10, 549–558 (2003). https://doi.org/10.1038/sj.cgt.7700598

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