Downregulation of indoleamine-2,3-dioxygenase in cervical cancer cells suppresses tumor growth by promoting natural killer cell accumulation

Sato, Naoto; Saga, Yasushi; Mizukami, Hiroaki; Wang, Dongdong; Takahashi, Suzuyo; Nonaka, Hiroaki; Fujiwara, Hiroyuki; Takei, Yuji; Machida, Shuichi; Takikawa, Osamu; Ozawa, Keiya; Suzuki, Mitsuaki

doi:10.3892/or.2012.1984

Cited by 38 publications

(23 citation statements)

References 30 publications

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“…IDO is the unique rate‐limiting enzyme of the kynurenine pathway and leads to trypotophan depletion, which is sensitive to T cells, making T cells have to stay in G 1 phase of cell cycle and fail to proliferate . Otherwise, the metabolites produced in alternative degradation of tryptophan are toxic for NK cells by preventing their accumulation and growth . Besides the direct inhibiting effect, IDO can up‐regulate the Foxp3 expression on traditional CD4 + T cells to induce their transformation to Tregs .…”

Section: Discussionmentioning

confidence: 99%

“…14 Otherwise, the metabolites produced in alternative degradation of tryptophan are toxic for NK cells by preventing their accumulation and growth. 15 Besides the direct inhibiting effect, IDO can up-regulate the Foxp3 expression on traditional CD4 1 T cells to induce their transformation to Tregs. 36 IDO is the main mechanism of sustaining the stability of Tregs, for it can block the conversion of Tregs to TH17-like cells, especially in TDLNs.…”

Section: Discussionmentioning

confidence: 99%

“…Indoleamine 2,3‐dioxygenase (IDO), a natural immune‐regulating enzyme, participates immune suppression and tolerance in various situations by inhitibing T cell and natural killer (NK) cell proliferation and activation . An increasing number of investigations have linked overexpression of IDO to carcinogenesis.…”

mentioning

confidence: 99%

“…Indoleamine 2,3-dioxygenase (IDO), a natural immuneregulating enzyme, participates immune suppression and tolerance in various situations by inhitibing T cell and natural killer (NK) cell proliferation and activation. 14,15 An increasing number of investigations have linked overexpression of IDO to carcinogenesis. High expressions of IDO are observed in patients with hepatocellular carcinoma, non-small cell lung cancer, colon cancer and invasive cervical carcinoma, leading to poor prognosis.…”

mentioning

confidence: 99%

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Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients

Jia

Wang

et al. 2015

Intl Journal of Cancer

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Indoleamine 2,3-dioxygenase (IDO) has been reported to be involved in esophageal squamous cell cancer (ESCC) progression by promoting immune escape. Previous studies have revealed bridging integrator-1 (Bin1) can inhibit cancer cell growth by suppressing expression of IDO, thus we investigated the correlation between the expression of Bin1 and IDO and their prognostic significances for ESCC patients. Specimens were collected from 196 ESCC patients and detected with flow cytometry, reverse transcription-polymerase chain reaction and immunohistochemistry. We found that in tumor microenvironment (TME) and tumor draining lymph node (TDLN), the proportions of CD3(+) CD4(+) T cell, CD3(+) CD8(+) T cell and CD3(-) CD16(+) CD56(+) NK cell were lower while the proportions of CD3(-) CD19(+) B cell and CD4(+) CD25(+) Treg were higher in specimens with high IDO expression when compared to the specimens with low IDO expression (p < 0.01). In addition, IDO expression was negatively correlated with Bin1 expression at gene and protein level in TME and TDLN. Both the expression of Bin1 and IDO were associated with some clinicopathological parameters including differentiation grade, TNM stage, invasion range, lymph node metastasis (p < 0.05). Moreover, multivariate survival analysis suggested that, along with some other parameters, low expression of Bin1 and high expression of IDO might be independent prognostic factor for ESCC patients. Our results demonstrate that low expression of Bin1, along with high expression of IDO, are predictor for poor prognosis in ESCC and thereby could be used to establish new therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients

Jia

Wang

et al. 2015

Intl Journal of Cancer

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“…24,25 Few studies have investigated the expression of IDO in cervical cancer. [26][27][28][29][30] Two such studies found higher levels of IDO expression in cervical cancer lesions as compared to normal cervical cells. 28,29 Fotopoulou et al, described less IDO activity in primary cervical cancer in comparison to samples from healthy individuals, but this study included only 20 patients.…”

Section: Introductionmentioning

confidence: 99%

Indoleamine-2,3-dioxygenase (IDO) metabolic activity is detrimental for cervical cancer patient survival

et al. 2015

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The expression of the immunomodulating enzyme indoleamine-2,3-dioxygenase (IDO) suppresses T-lymphocyte function, thus correlating with poor survival in a variety of cancer patients. IDO degrades the essential amino acid tryptophan leading to immunosuppressive kynurenines production. In the present study, concentrations of tryptophan, 3-hydroxykynurenine, and kynurenine were measured in pre-treatment serum samples of 251 cervical cancer patients by a mass-spectrometric method (XLC-MS/MS) and IDO activity determined by the kynurenine/tryptophan (Kyn/Trp) ratio. A low concentration of tryptophan was found to be significantly associated with tumors greater than 4 cm and lymph node metastatic spread. Furthermore, significant positive correlations were found between high concentrations of the tryptophan metabolites kynurenine and 3-hydroxykynurenine and advanced disease stage (FIGO >IIA) and lymph node metastases. High levels of kynurenine were further associated with parametrial invasion and tumor size. A high Kyn/Trp ratio was related to lymph node metastasis, FIGO stage, tumor size, parametrial invasion and poor disease-specific survival. These results suggest that IDO activation is linked to poor clinicopathological parameters and worse survival in cervical cancer, warranting the use of IDO inhibitors in future clinical trials.

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Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions

Spallanzani

Dalotto-Moreno

Iraolagoitia

et al. 2013

Cancer Immunol Immunother

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The progesterone analog medroxyprogesterone acetate (MPA) is widely used as a hormone replacement therapy in postmenopausal women and as contraceptive. However, prolonged administration of MPA is associated with increased incidence of breast cancer through ill-defined mechanisms. Here, we explored whether exposure to MPA during mammary tumor growth affects myeloid-derived suppressor cells (MDSCs; CD11b(+)Gr-1(+), mostly CD11b(+)Ly6G(+)Ly6C(int) and CD11b(+)Ly6G(-)Ly6C(high) cells) and natural killer (NK) cells, potentially restraining tumor immunosurveillance. We used the highly metastatic 4T1 breast tumor (which does not express the classical progesterone receptor and expands MDSCs) to challenge BALB/c mice in the absence or in the presence of MPA. We observed that MPA promoted the accumulation of NK cells in spleens of tumor-bearing mice, but with reduced degranulation ability and in vivo cytotoxic activity. Simultaneously, MPA induced a preferential expansion of CD11b(+)Ly6G(+)Ly6C(int) cells in spleen and bone marrow of 4T1 tumor-bearing mice. In vitro, MPA promoted nuclear mobilization of the glucocorticoid receptor (GR) in 4T1 cells and endowed these cells with the ability to promote a preferential differentiation of bone marrow cells into CD11b(+)Ly6G(+)Ly6C(int) cells that displayed suppressive activity on NK cell degranulation. Sorted CD11b(+)Gr-1(+) cells from MPA-treated tumor-bearing mice exhibited higher suppressive activity on NK cell degranulation than CD11b(+)Gr-1(+) cells from vehicle-treated tumor-bearing mice. Thus, MPA, acting through the GR, endows tumor cells with an enhanced capacity to expand CD11b(+)Ly6G(+)Ly6C(int) cells that subsequently display a stronger suppression of NK cell-mediated anti-tumor immunity. Our results describe an alternative mechanism by which MPA may affect immunosurveillance and have potential implication in breast cancer incidence.

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Downregulation of indoleamine-2,3-dioxygenase in cervical cancer cells suppresses tumor growth by promoting natural killer cell accumulation

Cited by 38 publications

References 30 publications

Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients

Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients

Indoleamine-2,3-dioxygenase (IDO) metabolic activity is detrimental for cervical cancer patient survival

Expansion of CD11b+Ly6G+Ly6Cint cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions

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