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

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-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), 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.

• Authors: Marion Wobser, Heike Voigt, Roland Houben, Andreas O Eggert, Matthias Freiwald, Ulrike Kaemmerer, Eckhart Kaempgen, David Schrama, Juergen C Becker
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 56 Issue 7 Pg. 1017-24 (Jul 2007) ISSN: 0340-7004 [Print] Germany
• PMID: 17195079 (Publication Type: Journal Article)

Chemical References

• Cancer Vaccines
• FOXP3 protein, human
• Forkhead Transcription Factors
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• RNA, Messenger
• Tryptophan

Topics

• Adult
• Animals
• Blotting, Western
• Cancer Vaccines (immunology, metabolism, therapeutic use)
• Dendritic Cells (enzymology, immunology)
• Female
• Forkhead Transcription Factors (metabolism)
• Humans
• Immunohistochemistry
• Immunotherapy
• Indoleamine-Pyrrole 2,3,-Dioxygenase (metabolism)
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism)
• Male
• Melanoma (immunology, therapy)
• Middle Aged
• RNA, Messenger (analysis)
• Reverse Transcriptase Polymerase Chain Reaction
• Tryptophan (metabolism)