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

Abstract

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that has immunoregulatory functions. Our prior study showed that tumoral IDO overexpression is involved in disease progression and impaired patient survival in human ovarian cancer, although its mechanism remains unclear. The purpose of the present study is to clarify the role of IDO during the process of peritoneal dissemination of ovarian cancer. Indoleamine 2,3-dioxygenase cDNA was transfected into the murine ovarian carcinoma cell line OV2944-HM-1, establishing stable clones of IDO-overexpressing cells (HM-1-IDO). Then HM-1-IDO or control vector-transfected cells (HM-1-mock) were i.p. transplanted into syngeneic immunocompetent mice. The HM-1-IDO-transplanted mice showed significantly shortened survival compared with HM-1-mock-transplanted (control) mice. On days 11 and 14 following transplantation, the tumor weight of peritoneal dissemination and ascites volume were significantly increased in HM-1-IDO-transplanted mice compared with those of control mice. 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. Therefore, IDO may be a promising molecular target for the therapeutic strategy of ovarian cancer.

1-butyltryptophan inhibits cell proliferation, migration, and invasion through the Akt pathway in human gastric cancer cells

“…Previous study also showed that phosphorylated Akt increased IDO expression in dendritic cells [20,21]. Furthermore, IDO expression was related with cancer metastasis [22,23]. Therefore, we speculated that 1-BT may also inhibit cell migration and invasion through suppressing the IDO expression in gastric cancer cells.…”

Novel inhibitor of brain indoleamine 2,3 dioxygenase, docking and experimental studies

“…IDO is frequently expressed in many cancers such as gastric, pancreatic, colorectal and prostate cancers (Uyttenhove, 2003), ovarian cancer (Tanazaki et al, 2014) and inflammation (Kim, 2015). To identify IDO inhibitors for therapeutic purpose we have selected IDO protein.…”

“…So, the induction of IDO by cytokines decreases the availability of TRP for serotonin synthesis (Mellor and Munn ,1999;Munn et al, 1999). Mostly IDO is expressed in many cancers like gastric, pancreatic, colorectal and prostate cancers (Uyttenhove, 2003), ovarian cancer (Tanazaki et al, 2014). The most common complication of cancer is cancer related fatigue (CRF) and its treatment that can significantly impair quality of life.…”

Aspects immunologiques du cancer de l’ovaire : perspectives thérapeutiques

“…IDO, en induisant un environnement immunosuppresseur, participerait à la diffusion intrapéritonéale des cancers de l'ovaire [183].…”