Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment.
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.
Affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.Show MeSH
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Mentions: Under steady-state conditions, HM-1 cells slightly expressed IDO protein, but it was markedly enhanced by the IFN-γ treatment (Fig. 1a), which is consistent with a previous study in other tumor cell lines.(25) In order to establish stable clones of IDO-overexpressing mouse ovarian cancer cells, we transfected mouse IDO cDNA into HM-1 cells and selected clones with high IDO expression (Fig. 1b). In the next step, we evaluated IDO enzymatic activity in these clones by measuring the concentrations of tryptophan and its main catabolite kynurenine in the conditioned medium. In clone 8, tryptophan was almost completely depleted, and reciprocally kynurenine was strongly produced after 48 h (Fig. 1c), suggesting that this clone had high tryptophan catabolizing activity. Thus, we used clone 8 as the IDO-overexpressing cells (HM-1-IDO) in the following experiments. Clones transfected with control vector (HM-1-mock) scarcely expressed IDO protein, and showed no enzymatic activity (Fig. 1b,c).
Affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.