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Inverse Correlation between Tumoral Indoleamine 2,3-Dioxygenase Expression and Tumor-Infiltrating Lymphocytes in Endometrial Cancer: Its Association with Disease Progression and Survival

Authors' Affiliations: ¹ Department of Obstetrics and Gynecology and ² Division of Pathology/Clinical Laboratory, Nagoya University Graduate School of Medicine, Nagoya, Japan and ³ 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: Tumor escape from host immune systems is a crucial mechanism for disease progression. We recently showed that the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) is a prognostic indicator for endometrial cancer. The purpose of the present study was to investigate the relationship between IDO expression and tumor-infiltrating lymphocytes (TIL) or natural killer (NK) cells and to clarify their prognostic effect in endometrial cancer.

Experimental Design: Immunohistochemical staining for IDO expression in endometrial cancer tissues (n = 65) was done. Tumor-infiltrating CD3+ and CD8+ lymphocytes, as well as CD57+ NK cells, were counted in serial tissue sections.

Results: High IDO expression in tumor cells was found in 32 of 65 cases and was positively correlated with myometrial invasion, nodal metastasis, and lymph-vascular space involvement. We also found a significant correlation between high IDO expression and reduced numbers of CD3+, CD8+, and CD57+ cells infiltrating into both the tumor epithelium and stroma. Patients with high IDO expression, a low number of stromal CD3 (<60), low intraepithelial CD8 (<25), or low stromal CD8 (<40) had significantly impaired progression-free survival. On multivariate analysis, IDO expression and the number of stromal CD3+ TILs were independent prognostic factors for impaired progression-free survival.

Conclusions: Tumoral IDO expression correlated with a reduced number of TILs and NK cells in endometrial cancer, possibly contributing to disease progression and impaired clinical outcome. These findings suggest that targeting IDO to restore host antitumor immunity may be a therapeutic strategy for endometrial cancer.