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: In order to explore the pathogenic roles of IDO in the tumor progression of ovarian cancer in vivo, HM-1-IDO or HM-1-mock cells were i.p. transplanted into B6C3F1 syngeneic mice, and used as a model of peritoneal dissemination of ovarian cancer. In HM-1-IDO-transplanted mice (HM-1-IDO group), the survival rate was significantly impaired compared with that of HM-1-mock-transplanted mice (HM-1-mock group; Fig. 2a). Actually, on day 14 after tumor cell injection, macroscopic findings showed that the tumor peritoneal dissemination was more evident and widespread in the HM-1-IDO group than in the HM-1-mock group (Fig. 2b). In parallel, histological findings indicated deep invasion of tumor cells into the peritoneum, resulting in much thicker peritoneum in the HM-1-IDO group (Fig. 2c,d). Consistently, the total weight of disseminated tumors in the HM-1-IDO group was significantly increased on day 14 compared with that in the HM-1-mock group (Fig. 2e). Moreover, on days 11 and 14 after tumor cell injection, the ascites volume was significantly larger in the HM-1-IDO group than in the HM-1-mock group (Fig. 2f). These observations implied that tumor-derived IDO could promote the peritoneal dissemination and progression of ovarian cancer.
Affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.