Indoleamine-2,3-dioxygenase, an immunosuppressive enzyme that inhibits natural killer cell function, as a useful target for ovarian cancer therapy

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

doi:10.3892/ijo.2011.1295

Cited by 68 publications

(54 citation statements)

References 37 publications

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“…75 Interestingly, IDO suppression has been shown to downregulate tumor growth and peritoneal dissemination in-vivo and promotes the accumulation of NK cells and their increased sensitivity to cancer cells in an in-vitro and in-vivo mouse model. 76 Similarly, an immunosuppressive effect of IDO has been reported on CD4C Th1 cells, CD8C T cells, and NK cells derived from peripheral blood, ascites, and tumors of ovarian cancer patients. 77 Trials are enrolling to test the use of IDO inhibitors in ovarian cancer patients at the time of diagnosis (NCT02042430) or have been proposed as a means to break IDO-induced tolerance, support cancer vaccination and promote anti-tumor immunity on patients with secondary disease (NCT01982487).…”

Section: Molecules Influencing Ovarian Til Functionmentioning

confidence: 82%

Tumor infiltrating lymphocytes in ovarian cancer

Santoiemma

Powell

2015

Cancer Biology & Therapy

295

229

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The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and geneengineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment. IntroductionTumor infiltrating lymphocytes (TILs) are present in ovarian cancer and are prognostic for increased survival. Given the impact of immunomodulatory regimens in melanoma, renal cell carcinoma, and lung cancer, and the recent elucidation of bona fide tumor-reactive TILs in ovarian cancer, the development of approaches that mobilize tumor-reactive TILs for successful eradication of ovarian cancer is now a high priority. In spite of strong rationale, attempts at administration of adoptive T cell transfer, immune enhancing antibody, and tumor immune environment conditioning in ovarian cancer have been minimal with some positive results reported in patients. In light of the recent development of new immunotherapeutic agents and treatment regimens that bolster host TIL activity, we review the current understanding of the immunobiology of human ovarian cancer including the impact of TIL subset accumulation on ovarian cancer survival and the effect of immune activation in the tumor microenvironment, and conclude that a new line of cancer immunotherapy investigations is warranted in ovarian carcinoma.Ovarian cancer is the second most common and most lethal gynecologic malignancy in the United States with approximately 22,000 new cases and 14,000 deaths expected in 2013.1 Ovarian cancer is often diagnosed at an advanced stage, with the large majority of new cases spread past the primary site. Since there are no current recommendations for ovarian cancer screenings, most efforts at combating ovarian cancer have been targeted at the discovery of new treatments rather than preventative measures. Currently, surgical staging and cytoreduction followed by chemotherapy is the mainstay of treatment, although in some cases neo-adjuvant chemotherapy is attempted.2 The standard for surgical staging consists of total hysterectomy and bilateral salpingooophrectomy with pelvic and para-aortic lymph node di...

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Section: Molecules Influencing Ovarian Til Functionmentioning

confidence: 82%

Tumor infiltrating lymphocytes in ovarian cancer

Santoiemma

Powell

2015

Cancer Biology & Therapy

295

229

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“…8 The levels of IDO protein at the fetal-maternal interface may generate a low L-tryptophan environment, which subsequently promotes immune pregnancy tolerance by inhibiting T cell and natural killer cell proliferation, or by inducing regulatory T cells and tolerogenic dendritic cells (DCs). 7,8,12,[38][39][40][41][42][43][44][45] It is possible that decreased activity or reduced levels of IDO protein may contribute to disorders of pregnancy such as RSA and pre-eclampsia.…”

Section: Groups Nmentioning

confidence: 99%

Indoleamine 2,3-dioxygenase levels at the normal and recurrent spontaneous abortion fetal–maternal interface

et al. 2013

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Objectives: To localize indoleamine 2,3-dioxygenase (IDO) mRNA and protein and to undertake a functional study at the first trimester fetal-maternal interface in order to determine whether the distribution and function of IDO are related to recurrent spontaneous abortion (RSA). Methods: Women undergoing legal pregnancy termination and women with RSA participated in this prospective study. Immunohistochemistry and real-time reverse transcription-polymerase chain reaction were used to analyse levels of IDO protein and mRNA in placenta, decidua and HTR-8/SVneo cells. Culture medium collected from trophoblast villous explant or HTR-8/SVneo cell cultures was used to measure IDO activity in response to interferon (IFN)-g treatment. Results: A total of 40 healthy women and 26 women with RSA provided samples of placenta and decidua. For normal pregnancies, IDO protein and mRNA was identified in placental trophoblasts, invasive extravillous trophoblasts and decidual glandular epithelium. IFN-g significantly increased IDO activity in trophoblast villous explants and HTR-8/SVneo cells. Levels of IDO protein and mRNA in the placenta and decidua from normal pregnancies were significantly higher than in those from RSA. Conclusions: Decreased levels of IDO protein and mRNA in the placenta and decidua from RSA suggest an important role for IDO in the maintenance of normal pregnancy.

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“…Overactivation of the kynurenine pathway results in a tryptophan decrease and kynurenine accumulation [1][2][3] . The former can result in the cell cycle arrest of immune cells, such as CD8+ T lymphocytes, natural killer (NK) cells, and invariant NK-T cells, via the general control non-depressible 2 stress kinase pathway and the mammalian target of rapamycin pathway [4][5][6] . The latter can cause the death of effector T cells due to the toxicity of its downstream product.…”

Section: Introductionmentioning

confidence: 99%

The Clinicopathological and Prognostic Significance of IDO1 Expression in Human Solid Tumors: Evidence from a Systematic Review and Meta-Analysis

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme catalyzing the initial and rate-limiting steps in the kynurenine pathway, which converts tryptophan into kynurenine. Upregulation of IDO1 decreases tryptophan levels and increases the accumulation of kynurenine and its metabolites. These metabolites can affect the proliferation of T cells. Increasing evidence has shown that IDO1 is highly expressed in various cancer types and associated with poor prognosis of cancer patients. However, the results were inconsistent. Methods: We searched the Web of Science, PubMed, Embase and Cochrane library databases to identify studies evaluating the prognostic value of IDO1 in cancer patients. Pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by using fixed-effects/random-effects models. Results: This systematic review and meta-analysis included 2706 patients from 24 articles. The results indicated a shorter overall survival in patients with high expression of IDO1 (hazard ratio [HR] = 2.03, 95% confidence interval [CI]: 1.56-2.63). Furthermore, disease-free survival was worse in patients with high expression of IDO1 (HR = 2.47, 95% CI: 1.46-4.20). Additionally, the pooled odds ratios (ORs) showed that increased IDO1 was significantly associated with tumor differentiation (OR = 1.81, 95% CI: 1.05-3.12), distant metastasis (OR = 1.45, 95% CI: 1.02-2.06), and poor clinical stage (OR = 1.89, 95% CI: 1.13-3.17). However, no significant correlation was observed of increased IDO1 expression with age, sex, lymph node metastasis, and tumor size. Conclusion: High expression of IDO1 is associated with poor clinical outcomes. IDO1 could serve as a biomarker of prognosis and a potential predictive factor of clinicopathology in various cancers. Further studies should be performed to verify the clinical utility of IDO1 in human solid tumors.

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Indoleamine-2,3-dioxygenase, an immunosuppressive enzyme that inhibits natural killer cell function, as a useful target for ovarian cancer therapy

Cited by 68 publications

References 37 publications

Tumor infiltrating lymphocytes in ovarian cancer

Tumor infiltrating lymphocytes in ovarian cancer

Indoleamine 2,3-dioxygenase levels at the normal and recurrent spontaneous abortion fetal–maternal interface

The Clinicopathological and Prognostic Significance of IDO1 Expression in Human Solid Tumors: Evidence from a Systematic Review and Meta-Analysis

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