CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition.
Immune tolerance is a central mechanism counteracting tumor-specific immunity and preventing effective anticancer immunotherapy. Induction of tolerance requires a specific environment in which tolerogenic dendritic cells (DCs) play an essential role deviating the immune response away from effective immunity. It was recently shown that maturation of DCs in the presence of PGE2 results in upregulation of indoleamine 2,3-dioxygenase (IDO) providing a potential mechanism for the development of DC-mediated Tcell 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 DCs induced IDO expression on transcriptional level, only integration of PGE2 signaling led to up-regulation 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 mediated mainly by IDO-induced tryptophan depletion. Of importance, 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 DCs in the tumor environment. We therefore suggest PGE2 to be a mediator of early events during induction of immune tolerance in cancer.
von Bergwelt-Baildon
Michael S
MS
Molecular Tumor Biology and Tumor Immunology, the Clinic I for Internal Medicine, Hematology and Oncology, the Institute of Neurophysiology, and the Institute for Pathology, University Hospital at the University of Cologne, Germany.
Popov
Alexey
A
Saric
Tomo
T
Chemnitz
Jens
J
Classen
Sabine
S
Stoffel
Marc S
MS
Fiore
Francesca
F
Roth
Udo
U
Beyer
Marc
M
Debey
Svenja
S
Wickenhauser
Claudia
C
Hanisch
Franz-Georg
FG
Schultze
Joachim L
JL
D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D015232:Dinoprostone / Q000494:pharmacology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; D015232:Dinoprostone