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

Takamatsu M, Hirata A, Ohtaki H, Hoshi M, Ando T, Ito H, Hatano Y, Tomita H, Kuno T, Saito K, Seishima M, Hara A - Cancer Sci. (2015)

Bottom Line: 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.Ido1 deficiency did not lead to significant differences in the size and number of colon tumors.Importantly, 1-mT treatment also significantly altered cytokine expression in the colon tumor tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.

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Related in: MedlinePlus

Effects of Ido1 deficiency on tumor-infiltrating lymphocytes in colon tumor tissues. (a) Immunohistochemical staining for Foxp3 (upper panels) and CD3 (lower panels) in colon tumors of ApcMin/+ mice. Scale bars: 100 μm (left panels) and 20 μm (right panels). (b,c) The densities of Foxp3-positive cells (Tregs), CD3-positive cells (T cells) and CD45R-positive cells (B-cells), the ratio of Foxp3-positive cells to CD3-positive cells assessed by immunohistochemistry (IHC), and the ratio of Foxp3/Cd3e mRNA expression assessed by quantitative PCR in tumor tissues of ApcMin/+ mice (b) and AOM/DSS-treated mice (c). Data are presented as the means ± SD. *P < 0.05 by Student’s t-test.
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fig04: Effects of Ido1 deficiency on tumor-infiltrating lymphocytes in colon tumor tissues. (a) Immunohistochemical staining for Foxp3 (upper panels) and CD3 (lower panels) in colon tumors of ApcMin/+ mice. Scale bars: 100 μm (left panels) and 20 μm (right panels). (b,c) The densities of Foxp3-positive cells (Tregs), CD3-positive cells (T cells) and CD45R-positive cells (B-cells), the ratio of Foxp3-positive cells to CD3-positive cells assessed by immunohistochemistry (IHC), and the ratio of Foxp3/Cd3e mRNA expression assessed by quantitative PCR in tumor tissues of ApcMin/+ mice (b) and AOM/DSS-treated mice (c). Data are presented as the means ± SD. *P < 0.05 by Student’s t-test.

Mentions: IDO promotes the differentiation of naive T cells into Tregs and the migration of Tregs, which is thought to be one of the key mechanisms of immunosuppression.27 Interestingly, a recent study showed the accumulation of regulatory T cells in intestinal tumors of ApcMin/+ mice.28 To clarify the effect of IDO deficiency on Treg infiltration in mouse colon tumors, we counted the number of lymphocytes that were positive for Foxp3 (a marker of Tregs) in tumor stroma by immunohistochemical analysis; and we then calculated the cellular density per unit area. In addition, expression of Foxp3 and Cd3e mRNA in the homogenized tumor tissue was assessed by real-time PCR to calculate the Foxp3/Cd3e ratio, which serves as a molecular indicator of the proportion of Tregs to total T-cell content. Immunohistochemically, Foxp3-positive lymphocytes were scattered in tumor stroma (Fig.4a). The density of Foxp3-positive lymphocytes in tumor stroma was significantly lower in Ido1(−/−) mice than in Ido1(+/+) mice, as determined after AOM/DSS treatment, whereas there were no significant differences between genotypes in the density of CD3-positive cells (Fig.4c). The ratio of Foxp3/CD3-positive cells was slightly lower in Ido1(−/−) mice than in Ido1(+/+) mice after treatment with AOM/DSS and the Foxp3/Cd3e mRNA expression ratio was lower, but the differences were not statistically significant (Fig.4c). Similarly, in ApcMin/+ mice, although no significant differences were observed, the Treg density was lower in Ido1(−/−) mice than in Ido1(+/+) mice (Fig.4b). Although there were fewer CD45R-positive cells than CD3-positive cells in the tumors, the density of CD45R-positive cells was significantly lower in Ido1(−/−) mice than in Ido1(+/+) mice after AOM/DSS treatment (Fig.4c). These results indicate that IDO1 deficiency can suppress the differentiation into Tregs and/or migration of Tregs, and, thus, reduce the Treg population in colon tumor tissue.


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

Takamatsu M, Hirata A, Ohtaki H, Hoshi M, Ando T, Ito H, Hatano Y, Tomita H, Kuno T, Saito K, Seishima M, Hara A - Cancer Sci. (2015)

Effects of Ido1 deficiency on tumor-infiltrating lymphocytes in colon tumor tissues. (a) Immunohistochemical staining for Foxp3 (upper panels) and CD3 (lower panels) in colon tumors of ApcMin/+ mice. Scale bars: 100 μm (left panels) and 20 μm (right panels). (b,c) The densities of Foxp3-positive cells (Tregs), CD3-positive cells (T cells) and CD45R-positive cells (B-cells), the ratio of Foxp3-positive cells to CD3-positive cells assessed by immunohistochemistry (IHC), and the ratio of Foxp3/Cd3e mRNA expression assessed by quantitative PCR in tumor tissues of ApcMin/+ mice (b) and AOM/DSS-treated mice (c). Data are presented as the means ± SD. *P < 0.05 by Student’s t-test.
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Related In: Results  -  Collection

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fig04: Effects of Ido1 deficiency on tumor-infiltrating lymphocytes in colon tumor tissues. (a) Immunohistochemical staining for Foxp3 (upper panels) and CD3 (lower panels) in colon tumors of ApcMin/+ mice. Scale bars: 100 μm (left panels) and 20 μm (right panels). (b,c) The densities of Foxp3-positive cells (Tregs), CD3-positive cells (T cells) and CD45R-positive cells (B-cells), the ratio of Foxp3-positive cells to CD3-positive cells assessed by immunohistochemistry (IHC), and the ratio of Foxp3/Cd3e mRNA expression assessed by quantitative PCR in tumor tissues of ApcMin/+ mice (b) and AOM/DSS-treated mice (c). Data are presented as the means ± SD. *P < 0.05 by Student’s t-test.
Mentions: IDO promotes the differentiation of naive T cells into Tregs and the migration of Tregs, which is thought to be one of the key mechanisms of immunosuppression.27 Interestingly, a recent study showed the accumulation of regulatory T cells in intestinal tumors of ApcMin/+ mice.28 To clarify the effect of IDO deficiency on Treg infiltration in mouse colon tumors, we counted the number of lymphocytes that were positive for Foxp3 (a marker of Tregs) in tumor stroma by immunohistochemical analysis; and we then calculated the cellular density per unit area. In addition, expression of Foxp3 and Cd3e mRNA in the homogenized tumor tissue was assessed by real-time PCR to calculate the Foxp3/Cd3e ratio, which serves as a molecular indicator of the proportion of Tregs to total T-cell content. Immunohistochemically, Foxp3-positive lymphocytes were scattered in tumor stroma (Fig.4a). The density of Foxp3-positive lymphocytes in tumor stroma was significantly lower in Ido1(−/−) mice than in Ido1(+/+) mice, as determined after AOM/DSS treatment, whereas there were no significant differences between genotypes in the density of CD3-positive cells (Fig.4c). The ratio of Foxp3/CD3-positive cells was slightly lower in Ido1(−/−) mice than in Ido1(+/+) mice after treatment with AOM/DSS and the Foxp3/Cd3e mRNA expression ratio was lower, but the differences were not statistically significant (Fig.4c). Similarly, in ApcMin/+ mice, although no significant differences were observed, the Treg density was lower in Ido1(−/−) mice than in Ido1(+/+) mice (Fig.4b). Although there were fewer CD45R-positive cells than CD3-positive cells in the tumors, the density of CD45R-positive cells was significantly lower in Ido1(−/−) mice than in Ido1(+/+) mice after AOM/DSS treatment (Fig.4c). These results indicate that IDO1 deficiency can suppress the differentiation into Tregs and/or migration of Tregs, and, thus, reduce the Treg population in colon tumor tissue.

Bottom Line: 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.Ido1 deficiency did not lead to significant differences in the size and number of colon tumors.Importantly, 1-mT treatment also significantly altered cytokine expression in the colon tumor tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.

Show MeSH
Related in: MedlinePlus