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

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.

[1]  B. Baban,et al.  Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. , 2007, The Journal of clinical investigation.

[2]  T. Shima,et al.  Expression of indoleamine 2, 3‐dioxygenase and the recruitment of Foxp3‐expressing regulatory T cells in the development and progression of uterine cervical cancer , 2007, Cancer science.

[3]  D. Munn,et al.  Indoleamine 2,3-dioxygenase and tumor-induced tolerance. , 2007, The Journal of clinical investigation.

[4]  Yoshimasa Tanaka,et al.  Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer , 2007, Proceedings of the National Academy of Sciences.

[5]  G. Prendergast,et al.  Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. , 2007, Cancer research.

[6]  L. Moretta,et al.  The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. , 2006, Blood.

[7]  H. Kajiyama,et al.  Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer , 2006, British Journal of Cancer.

[8]  T. Gajewski.  Identifying and Overcoming Immune Resistance Mechanisms in the Melanoma Tumor Microenvironment , 2006, Clinical Cancer Research.

[9]  Stefan Schneeberger,et al.  Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[10]  T. Whiteside,et al.  Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. , 2006, Seminars in cancer biology.

[11]  Gerd Ritter,et al.  Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[12]  O. Takikawa.  Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism. , 2005, Biochemical and biophysical research communications.

[13]  N. Yanaihara,et al.  Indoleamine 2,3-Dioxygenase Serves as a Marker of Poor Prognosis in Gene Expression Profiles of Serous Ovarian Cancer Cells , 2005, Clinical Cancer Research.

[14]  L. Mastracci,et al.  Eosinophil granulocytes account for indoleamine 2,3-dioxygenase-mediated immune escape in human non-small cell lung cancer. , 2005, Neoplasia.

[15]  G. Prendergast,et al.  Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy , 2005, Nature Medicine.

[16]  D. Munn,et al.  Ido expression by dendritic cells: tolerance and tryptophan catabolism , 2004, Nature Reviews Immunology.

[17]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[18]  B. Baban,et al.  Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. , 2004, The Journal of clinical investigation.

[19]  E. Sabo,et al.  Intratumoral CD8+ T Lymphocytes as a Prognostic Factor of Survival in Endometrial Carcinoma , 2004, Clinical Cancer Research.

[20]  H. Putter,et al.  Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis , 2004, Laboratory Investigation.

[21]  C. Uyttenhove,et al.  Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase , 2003, Nature Medicine.

[22]  George Coukos,et al.  Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. , 2003, The New England journal of medicine.

[23]  U. Grohmann,et al.  T cell apoptosis by tryptophan catabolism , 2002, Cell Death and Differentiation.

[24]  G. Damonte,et al.  Tryptophan-derived Catabolites Are Responsible for Inhibition of T and Natural Killer Cell Proliferation Induced by Indoleamine 2,3-Dioxygenase , 2002, The Journal of experimental medicine.

[25]  O. Takikawa,et al.  Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta. , 2002, Molecular human reproduction.

[26]  P. Koper,et al.  Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial , 2000, The Lancet.

[27]  S. Natsugoe,et al.  Prognostic value of intratumoral natural killer cells in gastric carcinoma , 2000, Cancer.

[28]  D. Munn,et al.  Prevention of allogeneic fetal rejection by tryptophan catabolism. , 1998, Science.

[29]  H Nagura,et al.  CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. , 1998, Cancer research.

[30]  M. A. Sáez,et al.  The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma , 1997, Cancer.

[31]  O. Takikawa,et al.  Mechanism of interferon-gamma action. Characterization of indoleamine 2,3-dioxygenase in cultured human cells induced by interferon-gamma and evaluation of the enzyme-mediated tryptophan degradation in its anticellular activity. , 1988, The Journal of biological chemistry.

[32]  S. Coca,et al.  Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. , 2002, Lung cancer.