title: Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses.
abstract: Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that contributes to tolerance in a number of biological settings. In cancer, IDO activity may help promote acquired tolerance to tumor antigens. The IDO inhibitor 1-methyl-tryptophan is being developed for clinical trials. However, 1-methyl-tryptophan exists in two stereoisomers with potentially different biological properties, and it has been unclear which isomer might be preferable for initial development. In this study, we provide evidence that the D and L stereoisomers exhibit important cell type-specific variations in activity. The L isomer was the more potent inhibitor of IDO activity using the purified enzyme and in HeLa cell-based assays. However, the D isomer was significantly more effective in reversing the suppression of T cells created by IDO-expressing dendritic cells, using both human monocyte-derived dendritic cells and murine dendritic cells isolated directly from tumor-draining lymph nodes. In vivo, the d isomer was more efficacious as an anticancer agent in chemo-immunotherapy regimens using cyclophosphamide, paclitaxel, or gemcitabine, when tested in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer. The D isomer of 1-methyl-tryptophan specifically targeted the IDO gene because the antitumor effect of D-1-methyl-tryptophan was completely lost in mice with a disruption of the IDO gene (IDO-knockout mice). Taken together, our findings support the suitability of D-1-methyl-tryptophan for human trials aiming to assess the utility of IDO inhibition to block host-mediated immunosuppression and enhance antitumor immunity in the setting of combined chemo-immunotherapy regimens.
authors.affiliation: Immunotherapy Center and Departments of Pediatrics, Medicine, and Biostatistics, Medical College of Georgia, Augusta, Georgia.
authors.forename: De-Yan
authors.initials: DY
authors.lastname: Hou
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Muller
authors.forename: Madhav D
authors.initials: MD
authors.lastname: Sharma
authors.forename: James
authors.initials: J
authors.lastname: DuHadaway
authors.forename: Tinku
authors.initials: T
authors.lastname: Banerjee
authors.forename: Maribeth
authors.initials: M
authors.lastname: Johnson
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D003713:Dendritic Cells / Q000201:enzymology*; D004357:Drug Synergism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000008:administration & dosage; D013237:Stereoisomerism; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; D003520:Cyclophosphamide; D017239:Paclitaxel