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Blood, 1 July 2006, Vol. 108, No. 1, pp. 228-237.
Prepublished online as a Blood First Edition Paper on March 7, 2006; DOI 10.1182/blood-2005-08-3507.
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Submitted August 31, 2005
Accepted February 16, 2006
CD25 and indoleamine 2,3-dioxygenase are upregulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo:additional mechanisms of T cell inhibition
Michael S von Bergwelt-Baildon, Alexey Popov, Tomo Saric, Jens M Chemnitz, Sabine Classen, Marc S Stoffel, Francesca Fiore, Udo Roth, Marc Beyer, Svenja Debey, Claudia Wickenhauser, Franz-Georg Hanisch, and Joachim L Schultze*
Molecular Tumor Biology and Tumor Immunology, University Hospital at the University of Cologne, Cologne, Germany; Clinic I for Internal Medicine, Hematology and Oncology, University Hospital at the University of Cologne, Cologne, Germany
Institute of Neurophysiology, University Hospital at the University of Cologne, Cologne, Germany
CologneInstitute for Pathology, University Hospital at the University of Cologne, Cologne, Germany
Molecular Tumor Biology and Tumor Immunology, University Hospital at the University of Cologne, Cologne, Germany
Institute for Biochemistry II, University Hospital at the University of Cologne, Cologne, Germany
* Corresponding author; email: joachim.schultze{at}uk-koeln.de.
Immune tolerance is a central mechanism counteracting tumor-specific immunity and preventing effective anti-cancer immunotherapy. Induction of tolerance requires a specific environment in which tolerogenic dendritic cells (DC) play an essential role deviating the immune response away from effective immunity. It was recently shown that maturation of DC in the presence of PGE2 results in upregulation of indoleamine 2,3-dioxygenase (IDO) providing a potential mechanism for the development of DC mediated T cell tolerance. Here we extend these findings, demonstrating a concomitant induction of IDO and secretion of soluble CD25 after DC maturation in the presence of PGE2. While maturation of DC induced IDO expression on transcriptional level, only integration of PGE2 signaling led to upregulation of functional IDO protein as well as significant expression of cell-surface and soluble CD25 protein. As a consequence, T cell proliferation and cytokine production were significantly inhibited, which was mainly mediated by IDO induced tryptophan depletion. Importantly, we demonstrate that different carcinoma entities associated with elevated levels of PGE2 coexpress CD25 and IDO in peritumoral dendritic cells, suggesting that PGE2 might influence IDO expression in human DC in the tumor environment. We therefore suggest PGE2 to be a mediator of early events during induction of immune tolerance in cancer.
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