Expression of Indoleamine 2,3-Dioxygenase In Carcinoma of Human Endometrium And Uterine Cervix

Sedlmayr, Peter; Semlitsch, Michaela; Gebru, Girmai; Karpf, E; Reich, Olaf; Tang, Tao; Wintersteiger, Reinhold; Takikawa, Osamu; Dohr, Gottfried

doi:10.1007/978-1-4615-0135-0_10

Cited by 17 publications

(11 citation statements)

References 9 publications

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“…Uyttenhove et al [31] described IDO in 25 different tumors. IDO has previously been detected in ovarian [31, 50] as well as endometrial tumors [29–31, 51, 52]. We have found high IDO expression in 21 % of primary endometrial tumors, which is in line with data reported by De Jong et al (18,1 %), but lower than the results obtained by Ino et al (46–49 %).…”

Section: Discussionsupporting

confidence: 91%

Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy

Vanderstraeten

Luyten

Verbist

et al. 2014

Cancer Immunol Immunother

110

101

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The major hurdle for cancer vaccines to be effective is posed by tumor immune evasion. Several common immune mechanisms and mediators are exploited by tumors to avoid immune destruction. In an attempt to shed more light on the immunosuppressive environment in uterine tumors, we analyzed the presence of PD-L1, PD-L2, B7-H4, indoleamine 2,3-dioxygenase (IDO), galectin-1, galectin-3, arginase-1 activity and myeloid-derived suppressor cell (MDSC) infiltration. IDO, PD-L1, PD-L2 and B7-H4 were analyzed by immunohistochemistry. PD-L2 was mostly expressed at low levels in these tumors. We found high IDO expression in 21 % of endometrial carcinoma samples and in 14 % of uterine sarcoma samples. For PD-L1 and B7-H4, we found high expression in 92 and 90 % of endometrial cancers, respectively, and in 100 and 92 % of the sarcomas. Galectin-1 and 3 were analyzed in tissue lysates by ELISA, but we did not find an increase in both molecules in tumor lysates compared with benign tissues. We detected expression of galectin-3 by fibroblasts, immune cells and tumor cells in single-cell tumor suspensions. In addition, we noted a highly significant increase in arginase-1 activity in endometrial carcinomas compared with normal endometria, which was not the case for uterine sarcomas. Finally, we could demonstrate MDSC infiltration in fresh tumor suspensions from uterine tumors. These results indicate that the PD-1/PD-L1 interaction and B7-H4 could be possible targets for immune intervention in uterine cancer patients as well as mediation of MDSC function. These observations are another step toward the implementation of inhibitors of immunosuppression in the treatment of uterine cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-014-1537-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy

Vanderstraeten

Luyten

Verbist

et al. 2014

Cancer Immunol Immunother

110

101

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“…TGF-beta is also upregulated at least two-fold in lymph node cervical cancer micrometastases [32]. Indoleamine 2,3-dioxygenase was also found at the invasion front of invasive cervical tumors and peritumoral stromal cells [33]. In the present work we found that NKp30 and NKp46 diminution was linked to HPV-16 infection.…”

Section: Discussionsupporting

confidence: 65%

Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions

et al. 2009

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BackgroundPersistent high risk HPV infection can lead to cervical cancer, the second most common malignant tumor in women worldwide. NK cells play a crucial role against tumors and virus-infected cells through a fine balance between activating and inhibitory receptors. Expression of triggering receptors NKp30, NKp44, NKp46 and NKG2D on NK cells correlates with cytolytic activity against tumor cells, but these receptors have not been studied in cervical cancer and precursor lesions. The aim of the present work was to study NKp30, NKp46, NKG2D, NKp80 and 2B4 expression in NK cells from patients with cervical cancer and precursor lesions, in the context of HPV infection.MethodsNKp30, NKp46, NKG2D, NKp80 and 2B4 expression was analyzed by flow cytometry on NK cells from 59 patients with cervical cancer and squamous intraepithelial lesions. NK cell cytotoxicity was evaluated in a 4 hour CFSE/7-AAD flow cytometry assay. HPV types were identified by PCR assays.ResultsWe report here for the first time that NK cell-activating receptors NKp30 and NKp46 are significantly down-regulated in cervical cancer and high grade squamous intraepithelial lesion (HGSIL) patients. NCRs down-regulation correlated with low cytolytic activity, HPV-16 infection and clinical stage. NKG2D was also down-regulated in cervical cancer patients.ConclusionOur results suggest that NKp30, NKp46 and NKG2D down-regulation represent an evasion mechanism associated to low NK cell activity, HPV-16 infection and cervical cancer progression.

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“…Consistently, Uyttenhove et al (2003) showed that IDO was expressed in the cancer cell itself, in a variety of human tumour types. In gynaecological malignancies, IDO expression was detected in cervical, endometrial, and ovarian cancers with a high rate of positivity, although a very limited number of samples were analysed in prior studies (Sedlmayr et al, 2003;Uyttenhove et al, 2003). Recently, Okamoto et al (2005) reported that IDO was expressed in 17 out of 24 cases with advanced ovarian carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer

et al. 2006

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Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolising enzyme inducing immune tolerance. The present study aimed to investigate IDO expression and its prognostic significance in endometrial cancer. Indoleamine 2,3-dioxygenase expression in endometrial cancer tissues (n ¼ 80) was immunohistochemically scored as four groups (IDOÀ, 1 þ , 2 þ , and 3 þ ). The high IDO expression (IDO2 þ or 3 þ ) in tumour cells was found in 37 (46.3%) of the 80 cases, and was positively correlated with surgical stage, myometrial invasion, lymph-vascular space involvement, and lymph node metastasis, but not with the histological grade. Patients with high IDO expression had significantly impaired overall survival and progression-free survival (PFS) (P ¼ 0.002 and P ¼ 0.001, respectively) compared to patients with no or weak expression of IDO (IDOÀ or 1 þ ). The 5-year PFS for IDOÀ/1 þ , 2 þ , and 3 þ were 97.7, 72.9, and 36.4%, respectively. Even in patients with early-stage disease (International Federation of Gynecology and Obstetrics I/II, n ¼ 64), the PFS for IDO2 þ /3 þ was significantly poor (P ¼ 0.001) compared to that for IDOÀ/1 þ . On multivariate analysis, IDO expression was an independent prognostic factor for PFS (P ¼ 0.020). These results indicated that the high IDO expression was involved in the progression of endometrial cancer and correlated with the impaired clinical outcome, suggesting that IDO is a novel and reliable prognostic indicator for endometrial cancer.

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Expression of Indoleamine 2,3-Dioxygenase In Carcinoma of Human Endometrium And Uterine Cervix

Cited by 17 publications

References 9 publications

Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy

Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy

Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions

Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer

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