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The escape of preneoplastic cells from the immune system, which is caused by immune tolerance, occurs during the development of several types of tumors. Indoleamine 2,3‐dioxygenase (IDO) plays a critical role in the induction of immune tolerance. In the present study we investigated the effects of 1‐methyltryptophan (1‐MT), an IDO inhibitor, and (−1;)‐epigallocatechin gallate (EGCG), the major catechin in green tea, on the development of azoxymethane (AOM)‐induced colonic preneoplastic lesions by focusing on the inhibition of IDO. To induce colonic premalignant lesions, male F344 rats were injected with AOM (20 mg/kg body weight, s.c.) once a week for 2 weeks. They also received 0.2% 1‐MT or 0.1% EGCG in their drinking water for 4 weeks, starting 1 week before the first dose of AOM. Both 1‐MT and EGCG significantly decreased the total number of aberrant crypt foci and β‐catenin‐accumulated crypts, which overexpressed IDO protein. Treatment with EGCG decreased IDO mRNA expression in both the colonic epithelium and stroma of rats induced by AOM. The AOM‐induced increase in cyclooxygenase‐2 mRNA expression in the colonic stroma was significantly decreased by EGCG. Furthermore, AOM‐induced increases in IDO activity in the serum and stroma were significantly inhibited by 1‐MT and EGCG. Inhibition of IDO activity by 1‐MT and EGCG was also observed in cell‐free assays. These findings suggest that upregulation of IDO activity is observed in the early stages of colon carcinogenesis and that the use of IDO inhibitors, such as 1‐MT and EGCG, which suppress the occurrence of colonic preneoplastic lesions, could be a novel strategy for the chemoprevention of colon cancer. (Cancer Sci 2012; 103: 951–958)

Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step in the metabolism of tryptophan along the kynurenine pathway. In tumors, increased IDO activity inhibits proliferation and induces apoptosis of T cells and natural killer cells. We investigated the therapeutic potential of IDO inhibitor 1-methyl- d -tryptophan ( d -1MT) with cyclophosphamide (CY) in a mouse model of lymphoma. To examine the effect of d -1MT, mice were killed on day 28. Serum concentrations of l -kynurenine and l -tryptophan were measured by high-performance liquid chromatography. Regulatory T cells (Tregs) were counted by flow cytometry, and mRNA expressions of IDO1, Foxp3, IFN-γ, and COX-2 were examined by quantitative real-time reverse transcription-polymerase chain reaction. d -1MT+CY combination treatment significantly inhibited tumor growth as compared to either treatment alone. There were no significant differences in the serum l -kynurenine/ l -tryptophan ratio or the IDO1 expression level in the tumors among the treatment groups. The expression levels of IFN-γ and COX-2 mRNA in tumor-draining lymph nodes (TDLNs) were found to be significantly up-regulated in the CY and d -1MT+CY groups. The number of Tregs in TDLNs in the d -1MT+CY group was significantly lower than that in CY groups on day 17. These results suggest that d -1MT in combination with CY is an effective treatment for lymphoma in a mouse model.

Hepatic immune regulation is associated with the progression from simple steatosis to non-alcoholic steatohepatitis, a severe condition of inflamed fatty liver. Indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that mediates the catabolism of L-tryptophan to L-kynurenine, plays an important role in hepatic immune regulation. In the present study, we examined the effects of IDO gene silencing on high-fat diet (HFD)-induced liver inflammation and fibrosis in mice. After being fed a HFD for 26 weeks, the IDO-knockout (KO) mice showed a marked infiltration of inflammatory cells, especially macrophages and T lymphocytes, in the liver. The expression levels of F4/80, IFNγ, IL-1β, and IL-6 mRNA in the liver and the expression levels of F4/80 and TNF-α mRNA in the white adipose tissue were significantly increased in IDO-KO mice, although hepatic steatosis, the accumulation of intrahepatic triglycerides, and the amount of oxidative stress were lower than those in IDO-wild-type mice. IDO-KO mice also developed marked pericellular fibrosis in the liver, accumulated hepatic hydroxyproline, and exhibited increased expression levels of hepatic TGF-β1 mRNA. These findings suggest that IDO-KO renders the mice more susceptible to HFD-induced hepatic inflammation and fibrosis. Therefore, IDO may have a protective effect against hepatic fibrosis, at least in this HFD-induced liver injury model.

Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing intracellular enzyme of the L-kynurenine pathway, causes preneoplastic cells and tumor cells to escape the immune system by inducing immune tolerance; this mechanism might be associated with the development and progression of human malignancies. In the present study, we investigated the role of IDO in diethylnitrosamine (DEN)-induced hepatocarcinogenesis by using IDO-knockout (KO) mice. To induce hepatocellular carcinoma (HCC), hepatic adenoma, and preneoplastic hepatocellular lesions termed foci of cellular alteration (FCA), male IDO-wild-type (WT) and IDO-KO mice with a C57BL/6J background received a single intraperitoneal injection of DEN at 2 weeks of age. The mice were sacrificed to evaluate the development of FCA and hepatocellular neoplasms. HCC overexpressed IDO and L-kynurenine compared to surrounding normal tissue in the DEN-treated IDO-WT mice. The number and cell proliferative activity of FCAs, and the incidence and multiplicity of HCC were significantly greater in the IDO-WT than in the IDO-KO mice. The expression levels of the IDO protein, of L-kynurenine, and of IFN-γ, COX-2, TNF-α, and Foxp3 mRNA were also significantly increased in the DEN-induced hepatic tumors that developed in the IDO-WT mice. The mRNA expression levels of CD8, perforin and granzyme B were markedly increased in hepatic tumors developed in IDO-KO mice. Moreover, Foxp3-positive inflammatory cells had infiltrated into the livers of DEN-treated IDO-WT mice, whereas fewer cells had infiltrated into the livers of IDO-KO mice. Induction of IDO and elevation of L-kynurenine might play a critical role in both the early and late phase of liver carcinogenesis. Our findings suggest that inhibition of IDO might offer a promising strategy for the prevention of liver cancer.

ObjectivesTo examine whether the extent of fibroproliferative changes on high-resolution CT (HRCT) scan influences prognosis, ventilator dependency and the associated outcomes in patients with early acute respiratory distress syndrome (ARDS).DesignA prospective observational cohort study.SettingIntensive care unit in a teaching hospital.Participants85 patients with ARDS who met American-European Consensus Conference Criteria and eligible criteria.InterventionsHRCT scans were performed and prospectively evaluated by two independent observers on the day of diagnosis and graded into six findings according to the extent of fibroproliferation. An overall HRCT score was obtained by previously published method.Primary and secondary outcomesThe primary outcome was 60-day mortality. Secondary outcomes included the number of ventilator-free days, organ failure-free days, the incidence of barotraumas and the occurrence of ventilator-associated pneumonia.ResultsHigher HRCT scores were associated with statistically significant decreases in organ failure-free days as well as ventilator-free days. Multivariate Cox proportional hazards model showed that the HRCT score remained an independent risk factor for mortality (HR 1.20; 95% CI 1.06 to 1.36; p=0.005). Multivariate analysis also revealed that the CT score had predictive value for ventilator weaning within 28 days (OR 0.63; 95% CI 0.48 to 0.82; p=0.0006) as well as for an incidence of barotraumas (OR 1.61; 95% CI 1.08 to 2.38; p=0.018) and for an occurrence of ventilator-associated pneumonia (OR 1.46; 95% CI 1.13 to 1.89; p=0.004). A HRCT score <210 enabled prediction of 60-day survival with 71% sensitivity and 72% specificity and of ventilator-weaning within 28 days with 75% sensitivity and 76% specificity.ConclusionsPulmonary fibroproliferation assessed by HRCT in patients with early ARDS predicts increased mortality with an increased susceptibility to multiple organ failure, including ventilator dependency and its associated outcomes.

Immune escape, the ability of tumor cells to avoid tumor-specific immune responses, occurs during the development and progression of several types of human malignancies, including colorectal cancer (CRC). Indoleamine 2,3-dioxygenase (IDO), the tryptophan catabolic enzyme, plays a significant role in regulating the immune response and provides tumor cells with a potent tool to evade the immune system. In the present study, we examined the effects of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, on the inhibition of IDO expression induced by interferon (IFN)-γ in human CRC cells. We found that IFN-γ increased the expression levels of IDO protein and mRNA in HT29 and SW837 CRC cell lines. Treatment of SW837 cells with EGCG significantly decreased IFN-γ-induced expression of IDO protein and mRNA in a dose-dependent manner. Enzymatic activity of IDO, determined by the concentration of L-kynurenine in the culture medium, was also significantly inhibited by EGCG treatment. Phosphorylation of signal transducer and activator of transcription 1 (STAT1) induced by IFN-γ was also significantly inhibited by EGCG. Reporter assays indicated that EGCG inhibited the transcriptional activities of IDO promoters, IFN-stimulated response element and IFN-γ activation sequence, activated by STAT1 phosphorylation. These findings suggest that EGCG may exert antitumor effects on CRC, at least in part, by inhibiting the expression and function of IDO through the suppression of STAT1 activation. EGCG may, thus, serve as a potential agent for antitumor immunotherapy and be useful in the chemoprevention and/or treatment of CRC.

Intracholecystic papillary neoplasm (ICPN) is a rare premalignant lesion of the gallbladder, and its natural history remains incompletely understood. We report a case of ICPN presenting as a small gallbladder polyp with progressive growth. A 56-year-old woman was found to have a gallbladder polyp measuring 7.6 mm, which increased to 11.2 mm over 2 years and 8 months. Contrast-enhanced computed tomography demonstrated a papillary lesion with enhancement. Laparoscopic cholecystectomy was performed. Histopathological examination revealed pyloric gland-type ICPN with low-grade dysplasia without invasive carcinoma. Immunohistochemical analysis showed positivity for MUC6 and MUC5AC, supporting gastric-type differentiation. No recurrence has been observed during postoperative follow-up.This case suggests that progressive growth, papillary morphology, and enhancement characteristics may indicate neoplastic potential even in gallbladder polyps initially measuring < 10 mm, suggesting the importance of careful follow-up and timely surgical intervention.

Although mismatch repair-deficient (dMMR)/microsatellite and instability-high (MSI-H) status is recognized as a biomarker that predicts the efficiency of immune checkpoint inhibitors (ICIs), the efficacy of ICIs treatment is still insufficient. Accordingly, insights into the mechanisms of acquired resistance to ICIs in gastrointestinal cancers are necessary, and developing immunotherapeutic strategies to improve response rates is an urgent clinical priority. We investigated the clinical characteristics of dMMR/MSI-H early gastric cancer and analyzed the expression patterns of immune checkpoint molecules within the tumor microenvironment. A total of 20 cases of early gastric cancer, treated between November 2019 and July 2024, were included. Immunohistochemistry was performed to assess the expression of mismatch repair (MMR) protein, and patient clinical characteristics were evaluated. Additionally, among the eight cases identified as dMMR early gastric cancer, they were further examined for the expression of immune checkpoint molecules in the tumor microenvironment using immunohistochemical staining. The median age of patients diagnosed with dMMR early gastric cancer was 73 years. In 20 patients, female sex and severe atrophy were associated with dMMR status in univariate analysis (OR 7.67, 95% CI 1.04-94.53). The expression pattern of immune checkpoint molecules showed heterogeneity. These findings highlight the heterogeneity of immune checkpoint expression patterns and provide preliminary, hypothesis-generating insights into variability in response to PD-1/PD-L1 blockade.

In this study, we aimed to evaluate the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) treatment for unresectable hepatocellular carcinoma (HCC) and to analyze the factors affecting overall survival (OS). A total of 69 patients who received Atez/Bev at our institutions for unresectable HCC were enrolled in this study. OS and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Changes in clinical indicators within 3 months were defined as delta (∆) values, and the Cox proportional hazards model was used to identify which ∆ values affected OS. The median OS, PFS, objective response rate, and disease control rate were 12.5 months, 5.4 months, 23.8%, and 71.4%, respectively. During the observational period, 62 patients (92.5%) experienced AEs (hypertension (33.3%) and general fatigue), and 27 patients (47.4%) experienced grade ≥ 3 AEs (hypertension (10.1%) and anemia (7.2%)). There was a significant deterioration in the albumin-bilirubin (ALBI) score (−2.22 to −1.97; p < 0.001), and a reduction in PIVKA-II levels (32,458 to 11,584 mAU/mL; p = 0.040) within 3 months after commencing Atez/Bev. Both the worsening ∆ ALBI score (p = 0.005) and increasing ∆ PIVKA-II (p = 0.049) were significantly associated with the OS of patients.

Adipose tissue is central to regulation of energy homeostasis. Adaptive thermogenesis, which relies on mitochondrial oxidative phosphorylation (Ox-Phos), dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to type 2 diabetes and obesity. Here, we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves glucose homeostasis by upregulation of Ox-Phos and reciprocal downregulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance and limited weight gain. NFIA up-regulates Ox-Phos and brown-fat-specific genes by enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulates proinflammatory cytokine genes to ameliorate adipose tissue inflammation. NFIA binds to regulatory region of the Ccl2 gene, which encodes proinflammatory cytokine MCP-1 (monocyte chemoattractant protein-1), to down-regulate its transcription. CCL2 expression was negatively correlated with NFIA expression in human adipose tissue. These results reveal the beneficial effect of NFIA on glucose and body weight homeostasis and also highlight previously unappreciated role of NFIA in suppressing adipose tissue inflammation.