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Dendritic cell based antitumor vaccination: impact of functional indoleamine 2,3-dioxygenase expression

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Abstract

Background

Recent reports have demonstrated that the enzyme indoleamine 2,3-dioxygenase (IDO) is upregulated in human dendritic cells (DCs) upon in vitro maturation. IDO is supposed to convey immunosuppressive effects by degrading the essential amino acid tryptophan, thereby downregulating T-cell functions. Hence, we evaluated IDO expression in DC preparations used for therapeutic DC vaccination and its in vivo effects.

Patients, methods and results

IDO expression was detected by real-time-PCR in a series of human clinical grade DCs (n = 28) prior to vaccination of advanced melanoma patients (n = 11). These analyses revealed an intra- and interpersonal variation in IDO mRNA levels. IDO was strongly upregulated in human DCs on RNA and on protein level upon in vitro maturation by Interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), Interleukin-6 (IL-6) and Prostaglandin E2 (PGE2) over a time course of 24 h. The enzymatic activity of induced IDO was demonstrated by measuring tryptophan degradation. Moreover, in biopsies obtained 24 h after application of the DC vaccine a prominent infiltrate of IDO-positive cells was observed by immunohistochemistry. The inflammatory infiltrate of these sites stained positive for the transcription factor Forkhead box P3 (FoxP3), suggesting an IDO-mediated induction of regulatory T-cells. All analysed melanoma patients (n = 11) receiving DC based immunotherapy exhibited rapid disease progression with a short overall survival due to advanced tumour stage.

Conclusion

The presented observations suggest a potential clinical relevance of IDO expression in DC-based therapeutic vaccines via the attraction or induction of FoxP3+ T-cells.

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Abbreviations

APC:

Antigen presenting cell

CTL:

Cytotoxic T-lymphocyte

DC:

Dendritic cell

FoxP3:

Forkhead box P3

GM-CSF:

Granulocyte monocyte colony stimulating factor

IDO:

Indoleamine 2,3-dioxygenase

IL:

Interleukin

PBMCs:

Peripheral blood mononuclear cells

PGE2:

Prostaglandin E2

Treg:

Regulatory T-cell

TGF-β:

Transforming growth factor-β

TNF-α:

Tumour necrosis factor-α

1MT:

1-Methyl-tryptophan

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Acknowledgments

We greatly thank Eva Baumann and Claudia Siedel, Department of Dermatology, University of Wuerzburg, Germany, for their excellent technical assistance and Claudia S. Kauczok for help with the immunohistochemical analysis. Furthermore, we thank Ulrich R. Hengge, University of Duesseldorf, Department of Dermatology, Germany, for providing the IDO antibody for immunohistochemistry.

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Authors and Affiliations

  1. Department of Dermatology, University of Wuerzburg, Josef-Schneider-Strasse 2, 97080, Wuerzburg, Germany

    Marion Wobser, Heike Voigt, Roland Houben, Andreas O. Eggert, David Schrama & Juergen C. Becker

  2. Institute of Pharmacy, Am Hubland, University of Wuerzburg, Wuerzburg, Germany

    Matthias Freiwald

  3. Department of Gynecology, University of Wuerzburg, Josef-Schneider Strasse 4, Wuerzburg, Germany

    Ulrike Kaemmerer

  4. Department of Dermatology, University of Erlangen, Hartmannstrasse 14, Erlangen, Germany

    Eckhart Kaempgen

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  1. Marion Wobser
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Correspondence to Juergen C. Becker.

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David Schrama and Juergen C. Becker contributed equally.

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Wobser, M., Voigt, H., Houben, R. et al. Dendritic cell based antitumor vaccination: impact of functional indoleamine 2,3-dioxygenase expression. Cancer Immunol Immunother 56, 1017–1024 (2007). https://doi.org/10.1007/s00262-006-0256-1

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  • DOI: https://doi.org/10.1007/s00262-006-0256-1

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