Induction of indoleamine-2,3 dioxygenase in bone marrow stromal cells inhibits myeloma cell growth.
OBJECTIVE
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme with immunoregulatory properties in cancer. By focusing on multiple myeloma cells and its microenvironment as potential sources of IDO, we aimed to delineate its influence on myeloma cell growth and survival and examine effector mechanisms.


METHODS
IDO expression was assessed in myeloma cells and in a coculture system with mesenchymal stromal cells (MSCs), including prior cytokine priming to induce IDO in MSCs. IDO expression was correlated with induction of apoptosis in myeloma cells and coupled with tryptophan depletion as well as rescue using IDO inhibitors.


RESULTS
We report low levels of expression of IDO in myeloma cell lines (MMCLs) and primary myeloma cells (MMCs), despite priming with interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), or hepatocyte growth factor (HGF). In MSCs, however, IDO could be functionally induced by IFN-γ, mediating apoptosis in myeloma cells following coculture. Addition of IDO-specific inhibitors, as well as addition of tryptophan, was shown to abrogate these effects.


CONCLUSIONS
IDO is expressed in primary MMCs to a low degree and is unlikely to play a direct major role in vivo in dampening antitumor immunity. However, cytokine stimulation of MSCs specifically induced IDO, which mediated a marked sensitivity of proximal myeloma cells to tryptophan depletion in the microenvironment, suggesting that selective measures to regulate its availability could be a useful strategy to achieve myeloma growth inhibition and apoptosis.
First Department of Medicine, Center for Oncology and Hematology, Wilhelminenspital, Montleartstrasse 37, 1160 Vienna, Austria.
Sabine
S
Pfeifer
Martin
M
Schreder
Arnold
A
Bolomsky
Sebastian
S
Graffi
Dietmar
D
Fuchs
Surinder S
SS
Sahota
Heinz
H
Ludwig
Niklas
N
Zojer
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013056:Spectrophotometry, Ultraviolet; D013867:Thiohydantoins / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007211:Indoles; D013867:Thiohydantoins; D014409:Tumor Necrosis Factor-alpha; C500233:methyl-thiohydantoin-tryptophan; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma; D014364:Tryptophan