Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice

Manabu Takamatsu, Akihiro Hirata, Hirofumi Ohtaki, Masato Hoshi, Tatsuya Ando, Hiroyasu Ito, Yuichiro Hatano, Hiroyuki Tomita, Toshiya Kuno, Kuniaki Saito, Mitsuru Seishima, Akira Hara

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 ApcMin/+ 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 ApcMin/+ 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.

Original languageEnglish
Pages (from-to)1008-1015
Number of pages8
JournalCancer Science
Volume106
Issue number8
DOIs
Publication statusPublished - 01-08-2015
Externally publishedYes

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Tumor Microenvironment
Colon
Neoplasms
Pharmacology
Azoxymethane
Cytokines
Tumor Escape
Kynurenine
Dextran Sulfate
Essential Amino Acids
Regulatory T-Lymphocytes
Tryptophan
Colonic Neoplasms
Colorectal Neoplasms
Carcinogenesis
Lymph Nodes
Clinical Trials
Messenger RNA
Enzymes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Takamatsu, Manabu ; Hirata, Akihiro ; Ohtaki, Hirofumi ; Hoshi, Masato ; Ando, Tatsuya ; Ito, Hiroyasu ; Hatano, Yuichiro ; Tomita, Hiroyuki ; Kuno, Toshiya ; Saito, Kuniaki ; Seishima, Mitsuru ; Hara, Akira. / Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice. In: Cancer Science. 2015 ; Vol. 106, No. 8. pp. 1008-1015.
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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 ApcMin/+ 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 ApcMin/+ 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.",
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Takamatsu, M, Hirata, A, Ohtaki, H, Hoshi, M, Ando, T, Ito, H, Hatano, Y, Tomita, H, Kuno, T, Saito, K, Seishima, M & Hara, A 2015, 'Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice', Cancer Science, vol. 106, no. 8, pp. 1008-1015. https://doi.org/10.1111/cas.12705

Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice. / Takamatsu, Manabu; Hirata, Akihiro; Ohtaki, Hirofumi; Hoshi, Masato; Ando, Tatsuya; Ito, Hiroyasu; Hatano, Yuichiro; Tomita, Hiroyuki; Kuno, Toshiya; Saito, Kuniaki; Seishima, Mitsuru; Hara, Akira.

In: Cancer Science, Vol. 106, No. 8, 01.08.2015, p. 1008-1015.

Research output: Contribution to journalArticle

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T1 - Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice

AU - Takamatsu, Manabu

AU - Hirata, Akihiro

AU - Ohtaki, Hirofumi

AU - Hoshi, Masato

AU - Ando, Tatsuya

AU - Ito, Hiroyasu

AU - Hatano, Yuichiro

AU - Tomita, Hiroyuki

AU - Kuno, Toshiya

AU - Saito, Kuniaki

AU - Seishima, Mitsuru

AU - Hara, Akira

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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 ApcMin/+ 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 ApcMin/+ 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.

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