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01.07.2007 | Original Article

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

verfasst von: Marion Wobser, Heike Voigt, Roland Houben, Andreas O. Eggert, Matthias Freiwald, Ulrike Kaemmerer, Eckhart Kaempgen, David Schrama, Juergen C. Becker

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 7/2007

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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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Titel: Dendritic cell based antitumor vaccination: impact of functional indoleamine 2,3-dioxygenase expression
verfasst von: Marion Wobser
Heike Voigt
Roland Houben
Andreas O. Eggert
Matthias Freiwald
Ulrike Kaemmerer
Eckhart Kaempgen
David Schrama
Juergen C. Becker
Publikationsdatum: 01.07.2007
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 7/2007
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-006-0256-1

Springer Medizin

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