IDO1 Expression Is Associated With Immune Tolerance and Poor Prognosis in Patients With Surgically Resected Esophageal Cancer

Kiyozumi, Yuki; Baba, Yoshifumi; Okadome, Kazuo; Yagi, Taisuke; Ishimoto, Takatsugu; Iwatsuki, Masaaki; Miyamoto, Yuji; Yoshida, Naoya; Watanabe, Masayuki; Komohara, Yoshihiro; Baba, Hideo

doi:10.1097/sla.0000000000002754

Cited by 75 publications

(69 citation statements)

References 40 publications

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“…These data indicate that CD169 is more predictive of a better clinical prognosis and high anti‐cancer immune activity than IDO1. Although the literature contains many research articles related to IDO1 in cancer, including esophageal cancer, we believe the present report is the first to describe the expression of IDO1 in LySMs. IDO1 plays a critical role in promoting the immune evasion of cancer cells, and recent clinical trials have focused on the anti‐cancer effects of IDO1 inhibitors .…”

Section: Discussionmentioning

confidence: 79%

High CD169 expression in lymph node macrophages predicts a favorable clinical course in patients with esophageal cancer

Takeya

Shiota

Yagi

et al. 2018

Pathology International

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Recent findings indicate CD169‐positive lymph node sinus macrophages (LySMs) in the regional lymph nodes (RLNs) play an important role in anti‐cancer immunity. In the present study, we investigated the correlation between CD169 expression in RLNs and clinicopathologic factors. Higher CD169 expression in LySMs was significantly associated with longer cancer‐specific survival (CSS). The density of tumor‐infiltrating lymphocytes (TILs) in the cancer nest and CD169 expression on LySMs were positively associated in patients who underwent pretreatment. As CD169 expression is thought to reflect a high interferon signature in RLNs, we tried to identify immunity‐related genes that are up‐regulated by interferon in macrophages as well as CD169. Indoleamine 2,3‐dioxygenase (IDO1) was found to be elevated by interferon, and expression of IDO1 was tested using immunohistochemistry. IDO1 expression on LySMs was positively correlated with CD169 expression; however, there was no significant correlation between IDO1 and clinicopathologic factors. These results suggest that high expression of CD169 in LySMs reflects a high potential for anti‐cancer immune responses in esophageal cancer patients and that monitoring CD169 expression would be useful for evaluating the potential of anti‐cancer immune reactions.

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Section: Discussionmentioning

confidence: 79%

High CD169 expression in lymph node macrophages predicts a favorable clinical course in patients with esophageal cancer

Takeya

Shiota

Yagi

et al. 2018

Pathology International

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“…In a previous study, we reported that IDO1 expression was associated with an unfavorable clinical outcome in esophageal cancer . Other studies have also reported on the relationship between IDO1 expression and clinical outcomes in several types of cancer (Table ).…”

Section: Introductionmentioning

confidence: 67%

“…The relationship between IDO1 promoter hypomethylation, preoperative therapy, and patient outcomes needs to be confirmed in independent cohorts in the future. As another point of view, we analyzed the relationship between IDO1 promoter methylation levels, presence of CD8+ TIL, and prognosis because we reported the importance of the role of CD8 + TIL for esophageal cancer in previous studies . However, we found no direct association between CD8 + TIL status (Figure ), IDO1 promoter methylation, and OS (Figure ).…”

Section: Discussionmentioning

confidence: 92%

“…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%

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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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“…Immunosuppression checkpoint molecules, including PD‐L1/PD‐1, galectin‐9/TIM‐3, IDO1, LAG‐3, and CTLA4, can inhibit the activation of effector T lymphocytes, ultimately leading to tumor immune escape 13,35 . Blocking these immunocheckpoints has become critical in cancer cell immunotherapy in recent years.…”

Section: Discussionmentioning

confidence: 99%

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

Guo

Lou

et al. 2020

Molecular Carcinogenesis

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Glioblastoma (GBM) is the most common and malignant brain tumor in adults. Recently, programmed death‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) checkpoint blockades have been applied for GBM treatment. However, the mechanism of PD‐L1 upregulation in GBM is still unclear. COP9 signalosome 6 (CSN6) is crucial for maintaining the protein stabilization in cancer cells. In this study, we applied human GBM specimens and cell lines to investigate whether the EGFR‐ERK pathway regulates CSN6 for PD‐L1 upregulation. Data from The Cancer Genome Atlas dataset showed that high expression of EGFR, CSN6, and PD‐L1 in patients with glioma was associated with poor prognosis. In 47 human GBM specimens, high expression of PD‐L1 was associated with low amount of CD8+ T cell infiltration as well as the poor prognosis of patients. CSN6 was positively correlated with EGFR and PD‐L1 expression in human GBM specimens. We treated two GBM cell lines (U87 and U251) with epidermal growth factor (EGF) in vitro, and found EGF‐upregulated p‐EGFR, p‐ERK, CSN6, and PD‐L1 expression in GBM cells. PD98059, the ERK blocker, inhibited upregulations of CSN6 and PD‐L1 in EGF‐treated cells. Inhibition of CSN6 by small interfering RNA decreased PD‐L1 expression but also increased CHIP expression in GBM cells. When the cells were treated with EGF and cycloheximide (CHX), a protein synthesis inhibitor, EGF‐reduced CHX‐induced CSN6 and PD‐L1 turnover in GBM cells. Furthermore, CSN6‐mediated downregulation of PD‐L1 was inhibited by MG132, a proteasome inhibitor in U87 cells. Thus, these results suggest that the EGFR‐ERK pathway may upregulate CSN6, which may inhibit PD‐L1 degradation and subsequently maintain PD‐L1 stability in GBM.

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IDO1 Expression Is Associated With Immune Tolerance and Poor Prognosis in Patients With Surgically Resected Esophageal Cancer

Abstract: IDO1 expression was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker. Combining the IDO1 and CD8 statuses enabled further classification of the clinical outcomes of patients.

Cited by 75 publications

References 40 publications

High CD169 expression in lymph node macrophages predicts a favorable clinical course in patients with esophageal cancer

High CD169 expression in lymph node macrophages predicts a favorable clinical course in patients with esophageal cancer

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

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

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