title: Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice.
abstract: Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades the essential amino acid l-tryptophan along the kynurenine pathway, exerts immunomodulatory effects in a number of diseases. IDO expression is increased in tumor tissue and in draining lymph nodes; this increase is thought to play a role in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for the treatment of relapsed or refractory solid tumors, but the efficacy of IDO inhibition in colorectal tumors remains to be fully elucidated. In this study, we investigated the effect of IDO deficiency on colon tumorigenesis in mice by genetic deletion and pharmacological inhibition. Ido1-deficient((-/-)) mice were crossed with Apc(Min/+) mice or were administered azoxymethane with or without dextran sodium sulfate. Ido1 deficiency did not lead to significant differences in the size and number of colon tumors. Similarly, the pharmacological inhibition of IDO using 1-methyltryptophan (1-mT) also resulted in no significant differences in tumor size and number in Apc(Min/+) mice. However, Ido1 deficiency altered the immune response in the tumor microenvironment, showing a significant increase in mRNA expression of pro-inflammatory cytokines and a significant decrease in the number of Foxp3-positive regulatory T cells in the colon tumors of Ido1((-/-)) mice. Importantly, 1-mT treatment also significantly altered cytokine expression in the colon tumor tissues. These results suggest that IDO inhibition alone cannot sufficiently suppress colon cancer development in mice despite its immunomodulatory activity in the tumor microenvironment.
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Takamatsu
authors.affiliation: Division of Animal Experiment, Life Science Research Center, Gifu University, Gifu, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirata
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohtaki
authors.affiliation: Faculty of Health Science, Suzuka University of Medical Science, Mie, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hoshi
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ando
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Hatano
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tomita
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Kuno
authors.affiliation: Human Health Sciences, Kyoto University Graduate School of Medicine and Faculty of Medicine, Kyoto, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D004791:Enzyme Inhibitors; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase
keywords: cancer immunity; colorectal cancer; indoleamine 2,3-dioxygenase; microenvironment; tumorigenesis