Indoleamine 2,3-dioxygenase 1 and overall survival of patients diagnosed with esophageal cancer

Rosenberg, Ari J.; Wainwright, Derek A.; Rademaker, Alfred; Galvez, Carlos; Genet, Matthew; Zhai, Lijie; Lauing, Kristen L.; Mulcahy, Mary F.; Hayes, John P.; Odell, David D.; Horbinski, Craig; Komanduri, Srinadh; Tétreault, Marie Pier; Kim, Kwang Youn; Villaflor, Victoria M.

doi:10.18632/oncotarget.25235

Cited by 19 publications

(24 citation statements)

References 48 publications

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“…In a previous study, we reported that IDO1 expression was associated with an unfavorable clinical outcome in esophageal cancer. 10 Other studies have also reported on the relationship between IDO1 expression and clinical outcomes in several types of cancer [11][12][13][14][15][16] ( Table 1). However, the molecular mechanisms that regulate IDO1 expression are not completely understood, including in esophageal cancer.…”

Section: Introductionmentioning

confidence: 99%

Indoleamine 2, 3‐dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer

et al. 2019

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Indoleamine 2, 3‐dioxygenase 1 ( IDO 1) is a primary enzyme that generates immunosuppressive metabolites. It plays a major role in tumor immunology and is a potential immune‐based therapeutic target. We have reported that IDO 1 protein expression was associated with an unfavorable clinical outcome in esophageal cancer. Recently, it has been reported that IDO 1 expression is regulated by methylation of the IDO 1 promoter. Thus, the aim of this study was to examine the relationship between IDO 1 expression, IDO 1 promoter methylation, and clinicopathological features in esophageal cancer. We first confirmed changes in IDO 1 expression levels in vitro by treating cells with 5‐azacytidine. We then evaluated the relationship between IDO 1 expression levels, IDO 1 promoter methylation (bisulfite pyrosequencing), and clinicopathological features using 40 frozen samples and 242 formalin‐fixed, paraffin‐embedded samples resected from esophageal cancer patients. We treated cell lines with 5‐azacytidine, and the resulting hypomethylation induced significantly higher IDO 1 expression ( P < .001). In frozen samples, IDO 1 expression levels correlated inversely with IDO 1 promoter methylation levels ( R = −0.47, P = .0019). Furthermore, patients in the IDO 1 promoter hypomethylation group (n = 67) had a poor prognosis compared with those in the IDO 1 promoter hypermethylation group (n = 175) (overall survival, P = .011). Our results showed that IDO 1 promoter hypomethylation regulated IDO 1 expression and was associated with a poor prognosis in esophageal cancer patients.

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Section: Introductionmentioning

confidence: 99%

Indoleamine 2, 3‐dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer

et al. 2019

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“…Thus, blocking of PD-L1/PD-1 is effective in the treatment of ESCC. However, the prognostic value of PD-L1 remains controversial [ 5 , 20 , 21 ]. PD-L1 can be expressed by a variety of cell types including tumor cells and stromal cells; whether PD-L1 expressed by different cells has different prognostic value is unknown.…”

Section: Introductionmentioning

confidence: 99%

A nomogram-based immunoprofile predicts overall survival for previously untreated patients with esophageal squamous cell carcinoma after esophagectomy

Duan

Xie

et al. 2018

j. immunotherapy cancer

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BackgroundImmunoscore, as a prognostic tool defined to quantify in situ immune cell infiltrates, appears to be superior to the TNM staging system. In esophageal squamous cell carcinoma (ESCC), no immunoscore has been established; however, in situ tumor immunology is recognized as highly important. Our study aimed to construct a comprehensive immunoprofile for ESCC.MethodsThe infiltration of four immune cell types (CD8+/CD4+/Foxp3+/CD33+ cells), the expression of both inhibitory (PD-1/PD-L1/Tim-3/LAG-3) and stimulatory checkpoints (OX-40/ICOS), and IDO1 were evaluated by IHC staining and multi-color immunofluorescence in two independent cohorts (95 patients in the primary cohort and 55 patients in the validation cohort). The association with patients’ overall survival was analyzed by the Kaplan-Meier method and the Cox model. Nomogram-based immunoprofile was established using the independent prognostic variables. To determine its predictive accuracy and discriminatory capacity, the C-index and calibration curve were calculated.ResultsSignificant correlation of PD-L1 expression in tumor cells with PD-1+ T cell infiltration was found (P = 0.035), indicating the activation of the inhibitory PD-1/PD-L1 pathway in ESCC cases. More PD-L1+ ICs, Tim-3+ ICs and LAG-3+ ICs were found in the CD8-rich tumor microenvironment, which is in accordance with the feedback nature of immune system. After adjustment by TNM stage, four immune variables including the infiltration of CD8+/Foxp3+/CD33+ cells and the PD-L1 expression by tumor cells were selected to construct a prognostic nomogram. The calibration curves showed good accuracy of the nomogram for survival prediction. To overcome the complexity of applying a nomogram in a clinical setting, a simple immunoprofile was then established according to the points of each factor from the nomogram. Our immunoprofile model could separate same-stage patients into different risk subgroups, and showed superior accuracy for survival prediction than the TNM staging system based on the C-index calculation and ROC analysis.ConclusionsOur nomogram-based immunoprofile can provide more accurate prognosis prediction and is an important complement to the TNM staging system for operable ESCC patients.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0418-7) contains supplementary material, which is available to authorized users.

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“…However, none of the B7 family molecules correlate with TDO expression in the liver while IDO shows a correlation with PD-L1 stronger than any other B7 family molecules. Correlation of IDO and PD-L1 has been shown in other tumors (55)(56)(57). Preclinical animal model studies also demonstrated that immune checkpoint blocking strategies with IDO targeting show an enhanced anti-tumor responses (58,59).…”

Section: Discussionmentioning

confidence: 90%

Correlation Patterns Among B7 Family Ligands and Tryptophan Degrading Enzymes in Hepatocellular Carcinoma

et al. 2020

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Mechanisms of dysfunctional T cell immunity in Hepatocellular Carcinoma (HCC) need to be well defined. B7 family molecules provide both co-stimulatory and co-inhibitory signals to T cells while tryptophan degrading enzymes like Indoleamine 2,3 dioxygenase (IDO) and Tryptophan 2,3 Dioxygenase (TDO) mediate tumor immune tolerance. It is necessary to identify their in situ correlative expression, which informs targets for combined immunotherapy approaches. We investigated B7 family molecules, IDO, TDO and immune responsive effectors in the tumor tissues of patients with HCC (n = 28) using a pathway-focused quantitative nanoscale chip real-time PCR. Four best correlative expressions, namely (1) B7-1 & PD-L2, (2) B7-H2 & B7-H3, (3) B7-2 & PD-L1, (4) PD-L1 & PD-L2, were identified among B7 family ligands, albeit they express at different levels. Although TDO expression is higher than IDO, PD-L1 correlates only with IDO but not TDO. Immune effector (Granzyme B) and suppressive (PD-1 and TGF-β) genes correlate with IDO and B7-1, B7-H5, PD-L2. Identification of the in situ correlation of PD-L1, PD-L2 and IDO suggest their cumulative immuno suppressive role in HCC. The distinct correlations among B7-1, B7-2, B7-H2, and B7-H3, correlation of PD-1 with non-cognate ligands such as B7-1 and B7-H5, and correlation of tumor lytic enzyme Granzyme B with IDO and PD-L2 suggest that HCC microenvironment is complexly orchestrated with both stimulatory and inhibitory molecules which together neutralize and blunt anti-HCC immunity. Functional assays demonstrate that both PDL-1 and IDO synergistically inhibit T cell responses. Altogether, the present data suggest the usage of combined immune checkpoint blocking strategies targeting co-inhibitory B7 molecules and IDO for HCC management.

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Indoleamine 2,3-dioxygenase 1 and overall survival of patients diagnosed with esophageal cancer

Cited by 19 publications

References 48 publications

Indoleamine 2, 3‐dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer

Indoleamine 2, 3‐dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer

A nomogram-based immunoprofile predicts overall survival for previously untreated patients with esophageal squamous cell carcinoma after esophagectomy

Correlation Patterns Among B7 Family Ligands and Tryptophan Degrading Enzymes in Hepatocellular Carcinoma

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