Elsevier

Gynecologic Oncology

Volume 117, Issue 3, June 2010, Pages 423-428
Gynecologic Oncology

Indoleamine 2,3-dioxygenase expression predicts impaired survival of invasive cervical cancer patients treated with radical hysterectomy

https://doi.org/10.1016/j.ygyno.2010.02.028Get rights and content

Abstract

Objective

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that induces tolerance to host immune surveillance within the tumor microenvironment. The present study aimed to investigate IDO expression and its prognostic significance in invasive cervical cancer.

Methods

Immunohistochemical expression of IDO in tumor tissues and its association with clinicopathological factors and survival were analyzed in 112 stage IB–IIB cervical cancer patients treated with radical hysterectomy and pelvic lymphadenectomy.

Results

IDO was diffusely expressed in tumor cells in 29 (26%) cases and focally expressed at the invasive front in 29 (26%) cases, while the other 54 (48%) cases were IDO-negative. IDO expression was positively correlated with clinical stage, lymph node metastasis, and lymph-vascular space invasion, but not with histological type. Patients with diffuse IDO expression had significantly reduced overall survival (OS) and disease-free survival (DFS) compared to patients with no IDO expression. The 5-year OS/DFS rates for the IDO-negative, focally positive, and diffusely positive groups were 92.3%/84.9%, 89.5%/75.8%, and 65.5%/51.7%, respectively. When we analyzed patients with stage IB disease alone (n = 67), the OS and DFS for the IDO-diffusely positive group were significantly lower than those for the IDO-negative group. In multivariate analysis, diffuse IDO expression was found to be an independent prognostic factor for impaired OS and DFS.

Conclusions

Diffuse expression of IDO in the tumor obtained from Stage IB–IIB cervical cancer patients who underwent radical hysterectomy was correlated with an unfavorable clinical outcome. These findings suggest that IDO may be a novel post-operative prognostic indicator for stage IB–IIB cervical cancer.

Introduction

Cervical cancer is the second most frequent cancer in women worldwide [1] and is generally treated by surgery, radiotherapy, or both. While primary concurrent chemoradiation therapy without surgery has recently been selected not only for advanced disease, but also for early-stage locally advanced disease [2], [3], [4], most patients with FIGO stage IB through IIB disease are treated with radical hysterectomy followed by adjuvant therapy at many institutions [5], [6], [7], [8]. Despite the generally good prognosis for stage IB–IIB cervical cancer, significant numbers of patients develop localized recurrence or distant metastases following surgery. Several clinicopathological parameters are currently used to assess the risk of relapse and death, including age, histological subtype, lymph node status, tumor size, depth of stromal invasion, parametrial invasion, and lymph-vascular space invasion (LVSI) [5], [6], [7], [8]. For patients belonging to high-risk groups, post-operative radiotherapy with or without chemotherapy has been performed. However, the selection of patients for adjuvant therapy and its effectiveness, especially its impact on survival, remain controversial [9]. Thus, in addition to the conventional clinicopathological parameters, the identification of molecular markers more closely related to the intrinsic biological behavior of cervical cancer and the individualization of adjuvant therapy based on more reliable prognostic indicators would be helpful for improving the survival of patients with this disease, as well as for preventing the unnecessary use of adjuvant therapy.

The development of cervical cancer is a multistep process initiated by persistent infection with human papillomavirus (HPV) [10]. After high-risk HPV infection, cervical lesions progress via cervical intraepithelial neoplasia (CIN) to invasive cervical cancer, in which most tumor cells constitutively express HPV-encoded E6 and E7 oncoproteins. Thus, host immune surveillance and its suppressive status within the tumor microenvironment are closely involved not only in cervical carcinogenesis [11], but also in further tumor growth and metastasis [12], [13], [14]. The presence of an immunosuppressive state within tumors involving the down-regulation of human leukocyte antigen (HLA) class I, production of immunosuppressive cytokines, and a low density of CD8+ tumor-infiltrating lymphocytes (TIL) combined with the induction of Foxp3+ regulatory T cells (Treg) was shown to be associated with disease progression and impaired survival in cervical cancer patients [15], [16], [17], [18]. In addition, recent studies have suggested that indoleamine 2,3-dioxygenase (IDO) is involved in the carcinogenesis of cervical cancer [11], [19].

IDO is a tryptophan-catabolizing enzyme that induces immune tolerance by depleting tryptophan and producing toxic tryptophan catabolites, which causes growth arrest of alloreactive T cells and natural killer (NK) cells and suppression of their killer function [20], [21], [22], [23]. In tumor-bearing mice, IDO was expressed in tumor cells and dendritic cells, both of which induce tolerance to tumor-derived antigens and also activation of Tregs [24], [25], [26], [27]. In human cancer, IDO expression was found to be associated with poor clinical outcome in colorectal cancer [28] and ovarian cancer [29]. Recently, we have demonstrated that IDO expression is correlated with disease progression and impaired patient survival in endometrial cancer and ovarian cancer, and that high tumoral IDO expression induces rapid tumor growth and spread together with the suppression of TIL and NK cells [30], [31], [32], [33]. These findings prompted us to investigate the expression of IDO in cervical cancer and its prognostic significance.

In the current study, we performed immunohistochemical analysis of IDO expression in cervical cancer and evaluated its correlation with clinicopathological factors and patient survival. We demonstrate here that IDO is a reliable molecular marker for predicting poor prognosis in invasive cervical cancer patients following radical hysterectomy.

Section snippets

Patient selection

One hundred and twelve patients with stage IB–IIB invasive cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy at Nagoya University Hospital between 1992 and 2003 were included in this study. All patients were staged according to the International Federation of Gynecology and Obstetrics (FIGO) criteria: 67 were stage IB, 10 were stage IIA, and 35 were stage IIB. Histological subtype was assigned according to the criteria of the World Health Organization (WHO)

Immunohistochemical expression of IDO in cervical cancer tissues

As shown in Fig. 1, IDO immunoreactivity was localized in the cytoplasm of cancer cells, while it was very faint or absent in the adjacent tumor–stromal cells. Of the 112 specimens examined, IDO was negative in 54 (48.2%) cases (Fig. 1A), focally expressed in 29 (25.9%) cases (Fig. 1B), and diffusely expressed in 29 (25.9%) cases (Fig. 1C). IDO was also markedly expressed in cervical adenocarcinoma cells (Fig. 1E and F). In contrast, IDO was not expressed in the normal cervical squamous

Discussion

In the present study, IDO was expressed in 52% of cases including SCC, AC, and ASC, which was consistent with the results shown by our prior studies in endometrial and ovarian cancers [30], [33]. We showed that IDO expression was correlated with FIGO stage, positive lymph node metastasis, and LVSI, but not with histological subtype. These results indicate that tumoral IDO is involved in the progression of cervical cancer in both SCC and AC.

The treatment options for cervical cancer differ

Conflict of interest statement

The authors declare that they have no conflicts of interest.

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