Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses

De Yan Hou, Alexander J. Muller, Madhav D. Sharma, James DuHadaway, Tinku Banerjee, Maribeth Johnson, Andrew L. Mellor, George C. Prendergast, David H. Munn

Research output: Contribution to journalArticle

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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 transplantanble 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.

Original languageEnglish (US)
Pages (from-to)792-801
Number of pages10
JournalCancer Research
Volume67
Issue number2
DOIs
StatePublished - Jan 15 2007

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Stereoisomerism
Dendritic Cells
gemcitabine
Immunotherapy
tryptophan methyl ester
Neoplasm Antigens
Enzymes
Immunosuppressive Agents
Paclitaxel
HeLa Cells
Knockout Mice
Antineoplastic Agents
Cyclophosphamide
Immunosuppression
Genes
Monocytes
Immunity
Melanoma
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. / Hou, De Yan; Muller, Alexander J.; Sharma, Madhav D.; DuHadaway, James; Banerjee, Tinku; Johnson, Maribeth; Mellor, Andrew L.; Prendergast, George C.; Munn, David H.

In: Cancer Research, Vol. 67, No. 2, 15.01.2007, p. 792-801.

Research output: Contribution to journalArticle

Hou, De Yan ; Muller, Alexander J. ; Sharma, Madhav D. ; DuHadaway, James ; Banerjee, Tinku ; Johnson, Maribeth ; Mellor, Andrew L. ; Prendergast, George C. ; Munn, David H. / Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. In: Cancer Research. 2007 ; Vol. 67, No. 2. pp. 792-801.
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AU - Banerjee, Tinku

AU - Johnson, Maribeth

AU - Mellor, Andrew L.

AU - Prendergast, George C.

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AB - 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 transplantanble 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.

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