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Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment.

Tanizaki Y, Kobayashi A, Toujima S, Shiro M, Mizoguchi M, Mabuchi Y, Yagi S, Minami S, Takikawa O, Ino K - Cancer Sci. (2014)

Bottom Line: This tumor-progressive effect was coincident with significantly reduced numbers of CD8(+) T cells and natural killer cells within tumors as well as increased levels of transforming growth factor-β and interleukin-10 in ascites.Finally, treatment with the IDO inhibitor 1-methyl-tryptophan significantly suppressed tumor dissemination and ascites with reduced transforming growth factor-β secretion.These findings showed that tumor-derived IDO promotes the peritoneal dissemination of ovarian cancer through suppression of tumor-infiltrating effector T cell and natural killer cell recruitment and reciprocal enhancement of immunosuppressive cytokines in ascites, creating an immunotolerogenic environment within the peritoneal cavity.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.

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Immunohistochemical detection of indoleamine 2,3-dioxygenase (IDO)+ cells (a), CD8+ cells (b), natural killer (NK) cells (c), and α-smooth muscle actin (α-SMA)+ myofibroblasts (d) in the tumor microenvironment of mice transplanted with control vector-transfected (HM-1-mock) and IDO-overexpressing (HM-1-IDO) OV2944-HM-1 cells (on day 14). Representative results from six independent experiments are shown. Arrowheads indicate positive cells. Original magnification, ×400. Bar = 50 μm. (e–g) Enumeration of tumor-infiltrating CD8+ T cells (e), NK cells (f) and α-SMA+ myofibroblasts (g) on day 14. All values represent mean ± SD. *P < 0.05, HM-1-mock versus HM-1-IDO.
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fig03: Immunohistochemical detection of indoleamine 2,3-dioxygenase (IDO)+ cells (a), CD8+ cells (b), natural killer (NK) cells (c), and α-smooth muscle actin (α-SMA)+ myofibroblasts (d) in the tumor microenvironment of mice transplanted with control vector-transfected (HM-1-mock) and IDO-overexpressing (HM-1-IDO) OV2944-HM-1 cells (on day 14). Representative results from six independent experiments are shown. Arrowheads indicate positive cells. Original magnification, ×400. Bar = 50 μm. (e–g) Enumeration of tumor-infiltrating CD8+ T cells (e), NK cells (f) and α-SMA+ myofibroblasts (g) on day 14. All values represent mean ± SD. *P < 0.05, HM-1-mock versus HM-1-IDO.

Mentions: In the next series, we immunohistochemically examined the recruitment of CD8+ TILs and NK cells that were essentially involved in tumor immunity. In HM-1-IDO-transplanted mice, the IDO-positive signals in tumor cells were confirmed within the disseminated tumors, whereas they were not observed in the HM-1-mock group (Fig. 3a). The number of CD8+ TILs and NK cells within the tumors was significantly reduced in the HM-1-IDO group, compared with that in the HM-1-mock group (Fig. 3b,c,e,f). These observations suggested that IDO overexpression could suppress the recruitment of CD8+ TILs and NK cells into the tumor microenvironment. In contrast, the number of α-SMA+ myofibroblasts in the tumor stroma was significantly increased in the HM-1-IDO group, compared to that in the HM-1-mock group (Fig. 3d,g).


Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment.

Tanizaki Y, Kobayashi A, Toujima S, Shiro M, Mizoguchi M, Mabuchi Y, Yagi S, Minami S, Takikawa O, Ino K - Cancer Sci. (2014)

Immunohistochemical detection of indoleamine 2,3-dioxygenase (IDO)+ cells (a), CD8+ cells (b), natural killer (NK) cells (c), and α-smooth muscle actin (α-SMA)+ myofibroblasts (d) in the tumor microenvironment of mice transplanted with control vector-transfected (HM-1-mock) and IDO-overexpressing (HM-1-IDO) OV2944-HM-1 cells (on day 14). Representative results from six independent experiments are shown. Arrowheads indicate positive cells. Original magnification, ×400. Bar = 50 μm. (e–g) Enumeration of tumor-infiltrating CD8+ T cells (e), NK cells (f) and α-SMA+ myofibroblasts (g) on day 14. All values represent mean ± SD. *P < 0.05, HM-1-mock versus HM-1-IDO.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4317851&req=5

fig03: Immunohistochemical detection of indoleamine 2,3-dioxygenase (IDO)+ cells (a), CD8+ cells (b), natural killer (NK) cells (c), and α-smooth muscle actin (α-SMA)+ myofibroblasts (d) in the tumor microenvironment of mice transplanted with control vector-transfected (HM-1-mock) and IDO-overexpressing (HM-1-IDO) OV2944-HM-1 cells (on day 14). Representative results from six independent experiments are shown. Arrowheads indicate positive cells. Original magnification, ×400. Bar = 50 μm. (e–g) Enumeration of tumor-infiltrating CD8+ T cells (e), NK cells (f) and α-SMA+ myofibroblasts (g) on day 14. All values represent mean ± SD. *P < 0.05, HM-1-mock versus HM-1-IDO.
Mentions: In the next series, we immunohistochemically examined the recruitment of CD8+ TILs and NK cells that were essentially involved in tumor immunity. In HM-1-IDO-transplanted mice, the IDO-positive signals in tumor cells were confirmed within the disseminated tumors, whereas they were not observed in the HM-1-mock group (Fig. 3a). The number of CD8+ TILs and NK cells within the tumors was significantly reduced in the HM-1-IDO group, compared with that in the HM-1-mock group (Fig. 3b,c,e,f). These observations suggested that IDO overexpression could suppress the recruitment of CD8+ TILs and NK cells into the tumor microenvironment. In contrast, the number of α-SMA+ myofibroblasts in the tumor stroma was significantly increased in the HM-1-IDO group, compared to that in the HM-1-mock group (Fig. 3d,g).

Bottom Line: This tumor-progressive effect was coincident with significantly reduced numbers of CD8(+) T cells and natural killer cells within tumors as well as increased levels of transforming growth factor-β and interleukin-10 in ascites.Finally, treatment with the IDO inhibitor 1-methyl-tryptophan significantly suppressed tumor dissemination and ascites with reduced transforming growth factor-β secretion.These findings showed that tumor-derived IDO promotes the peritoneal dissemination of ovarian cancer through suppression of tumor-infiltrating effector T cell and natural killer cell recruitment and reciprocal enhancement of immunosuppressive cytokines in ascites, creating an immunotolerogenic environment within the peritoneal cavity.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.

Show MeSH
Related in: MedlinePlus