Efficacy of levo-1-methyl tryptophan and dextro-1-methyl tryptophan in reversing indoleamine-2,3-dioxygenase-mediated arrest of T-cell proliferation in human epithelial ovarian cancer.
It has been reported that levo-1-methyl tryptophan (L-1MT) can block indoleamine-2,3-dioxygenase (IDO) expressed by human dendritic cells (DC), whereas dextro-1-methyl tryptophan (D-1MT) is inefficient. However, whether L-1MT or D-1MT can efficiently reverse IDO-induced arrest of human T-cell proliferation has not been clarified. Here, we show a marked immunosuppressive effect of IDO derived from INDO-transfected 293 cell, IDO+ ovarian cancer cells, and monocyte-derived DCs on CD4+ Th1 cells, CD8+ T cells, and natural killer cells derived from peripheral blood, ascites, and tumors of ovarian cancer patients. We found that, whereas L-1MT and D/L-1MT can restore proliferation of tumor-derived and peripheral blood T-cell subsets, D-1MT does not effectively restore IDO-induced arrest of T-cell proliferation. Although D-1MT inhibited kynurenine production at high concentrations, L-1MT was more effective in abrogating kynurenine generation and tryptophan depletion, whereas tryptophan was completely depleted by IDO even in the presence of high amounts of D-1MT. Together, the results indicate that, whereas the generation of tryptophan metabolites (kynurenines) by IDO is important in mediating suppression of T-cell proliferation, the degree to which tryptophan depletion is restored by 1MT is also critical in overcoming IDO-induced arrest of T-cell proliferation.
Qian
Feng
F
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Villella
Jeannine
J
Wallace
Paul K
PK
Mhawech-Fauceglia
Paulette
P
Tario
Joseph D
JD
Andrews
Christopher
C
Matsuzaki
Junko
J
Valmori
Danila
D
Ayyoub
Maha
M
Frederick
Peter J
PJ
Beck
Amy
A
Liao
Jianqun
J
Cheney
Richard
R
Moysich
Kirsten
K
Lele
Shashikant
S
Shrikant
Protul
P
Old
Lloyd J
LJ
Odunsi
Kunle
K
D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D007668:Kidney; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014162:Transfection; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; C525396:1-methyltryptophan