In vivo metabolism of tryptophan in meningiomas is mediated by indoleamine 2,3-dioxygenase 1.
Expression and activity of indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting step of the kynurenine pathway of tryptophan catabolism, can enable tumor cells to effectively evade the host's immune response. The potential role of this system was investigated in meningiomas. Surgical specimens from 22 patients with meningiomas were used for cellular, immunological and molecular techniques (immunofluorescence, western blotting, RT-PCR and biochemical assay of enzyme activity) to investigate the expression and activity of IDO. In addition, PET imaging was obtained preoperatively in 10 patients using the tracer α-[ ( 11) C]methyl-L-tryptophan (AMT) which interrogates the uptake and metabolism of tryptophan. Strong AMT accumulation was noted in all meningiomas by PET imaging indicating in vivo tryptophan uptake. Freshly-resected meningiomas expressed both LAT1, the tryptophan transporter system and IDO, demonstrating an active kynurenine pathway. Dissociated meningioma cells lost IDO expression. Following exposure to interferon-γ (IFNγ), IDO expression was reinduced and could be blocked by a selective IDO1 inhibitor. IDO activity may represent an element of local self-protection by meningiomas and could be targeted by emerging IDO1 inhibitors.
Department of Neurosurgery, Wayne State University, Detroit, MI, USA.
Ian M
IM
Zitron
David O
DO
Kamson
Sam
S
Kiousis
Csaba
C
Juhász
Sandeep
S
Mittal
D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D027283:Large Neutral Amino Acid-Transporter 1 / Q000096:biosynthesis; D008577:Meningeal Neoplasms / Q000000981:diagnostic imaging / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008579:Meningioma / Q000000981:diagnostic imaging / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography; D014364:Tryptophan / Q000378:metabolism*
C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D027283:Large Neutral Amino Acid-Transporter 1; D007371:Interferon-gamma; D014364:Tryptophan
1-methyl-tryptophan; alpha-[11C]methyl-L-tryptophan PET; immunosuppression; indoleamine 2,3-dioxygenase; interferon-gamma; meningioma; tryptophan metabolism