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Overexpression of Indoleamine 2,3-Dioxygenase in Human Endometrial Carcinoma Cells Induces Rapid Tumor Growth in a Mouse Xenograft Model

Authors' Affiliations: ¹ Department of Obstetrics and Gynecology, ² Department of Immunology, and ³ Radioisotope Research Center, Nagoya University Graduate School of Medicine, Nagoya, Japan; ⁴ Department of Photobiology, Research Center for Cooperative Projects, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and ⁵ National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Japan

Requests for reprints: Kazuhiko Ino, Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Phone: 81-52-744-2261; Fax: 81-52-744-2268; E-mail: kazuino{at}med.nagoya-u.ac.jp.

Purpose: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that induces immune tolerance in mice. Our prior study showed that high tumoral IDO expression in endometrial cancer tissues correlates with disease progression and impaired patient survival. The purpose of the present study was to clarify the functional role of IDO in human endometrial cancer cells and to investigate the therapeutic potential of IDO inhibitors.

Experimental Design: IDO cDNA was transfected into the human endometrial carcinoma cell line AMEC, resulting in the establishment of stable clones of IDO-overexpressing AMEC cells (AMEC-IDO). AMEC-IDO cells were characterized in vitro as well as in vivo using a mouse xenograft model.

Results: There was no significant difference in in vitro cell proliferation, migration, or chemosensitivity to paclitaxel between AMEC-IDO and control vector–transfected cells (AMEC-pcDNA). However, in vivo tumor growth was markedly enhanced in AMEC-IDO–xenografted nude mice when compared with AMEC-pcDNA–xenografted mice. Splenic natural killer (NK) cell counts in AMEC-IDO–xenografted mice were significantly decreased when compared with control mice. Furthermore, conditioned medium obtained from AMEC-IDO cell cultures markedly reduced the NK lysis activity of nude mice. Finally, oral administration of the IDO inhibitor 1-methyl-D-tryptophan in combination with paclitaxel in AMEC-IDO–xenografted mice strongly potentiated the antitumor effect of paclitaxel, resulting in significantly prolonged survival.

Conclusions: This is the first evidence showing that IDO overexpression in human cancer cells contributes to tumor progression in vivo with suppression of NK cells. Our data suggest that targeting IDO may be a novel therapeutic strategy for endometrial cancer.