Lung-Protective Ventilation for Pediatric Acute Respiratory Distress Syndrome: A Nonrandomized Controlled Trial.

OBJECTIVES: Despite the recommendation for lung-protective mechanical ventilation (LPMV) in pediatric acute respiratory distress syndrome (PARDS), there is a lack of robust supporting data and variable adherence in clinical practice. This study evaluates the impact of an LPMV protocol vs. standard care and adherence to LPMV elements on mortality. We hypothesized that LPMV strategies deployed as a pragmatic protocol reduces mortality in PARDS. DESIGN: Multicenter prospective before-and-after comparison design study. SETTING: Twenty-one PICUs. PATIENTS: Patients fulfilled the Pediatric Acute Lung Injury Consensus Conference 2015 definition of PARDS and were on invasive mechanical ventilation. INTERVENTIONS: The LPMV protocol included a limit on peak inspiratory pressure (PIP), delta/driving pressure (DP), tidal volume, positive end-expiratory pressure (PEEP) to Fio2 combinations of the low PEEP acute respiratory distress syndrome network table, permissive hypercarbia, and conservative oxygen targets. MEASUREMENTS AND MAIN RESULTS: There were 285 of 693 (41·1%) and 408 of 693 (58·9%) patients treated with and without the LPMV protocol, respectively. Median age and oxygenation index was 1.5 years (0.4-5.3 yr) and 10.9 years (7.0-18.6 yr), respectively. There was no difference in 60-day mortality between LPMV and non-LPMV protocol groups (65/285 [22.8%] vs. 115/406 [28.3%]; p = 0.104). However, total adherence score did improve in the LPMV compared to non-LPMV group (57.1 [40.0-66.7] vs. 47.6 [31.0-58.3]; p < 0·001). After adjusting for confounders, adherence to LPMV strategies (adjusted hazard ratio, 0.98; 95% CI, 0.97-0.99; p = 0.004) but not the LPMV protocol itself was associated with a reduced risk of 60-day mortality. Adherence to PIP, DP, and PEEP/Fio2 combinations were associated with reduced mortality. CONCLUSIONS: Adherence to LPMV elements over the first week of PARDS was associated with reduced mortality. Future work is needed to improve implementation of LPMV in order to improve adherence.

An algorithm-based technique for counting mitochondria in cells using immunohistochemical staining of formalin-fixed and paraffin-embedded sections.

PURPOSE: Visualizing mitochondria in cancer cells from human pathological specimens may improve our understanding of cancer biology. However, using immunohistochemistry to evaluate mitochondria remains difficult because almost all cells contain mitochondria and the number of mitochondria per cell may have important effects on mitochondrial function. Herein, we established an objective system (Mito-score) for evaluating mitochondria using machine-based processing of hue, saturation, and value color spaces. METHODS: The Mito-score was defined as the number of COX4 (mitochondrial inner membrane) immunohistochemistry-positive pixels divided by the number of nuclei per cell. The system was validated using four lung cancer cell lines, normal tissues, and lung cancer tissues (199 cases). RESULTS: The Mito-score correlated with MitoTracker, a fluorescent dye used to selectively label and visualize mitochondria within cells under a microscope (R2 = 0.68) and with the number of mitochondria counted using electron microscopy (R2 = 0.79). Histologically, the Mito-score of small cell carcinoma (57.25) was significantly lower than that of adenocarcinoma (147.5, p < 0.0001), squamous cell carcinoma (120.6, p = 0.0004), and large cell neuroendocrine carcinoma (111.8, p = 0.002). CONCLUSION: The Mito-score method enables the analysis of the mitochondrial status of human formalin-fixed paraffin-embedded specimens and may provide insights into the metabolic status of cancer.

Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments.

Overcoming resistance to immune checkpoint inhibitors is an important issue in patients with non-small-cell lung cancer (NSCLC). Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI), and squamous cell carcinoma (LUSQ) into four. However, the immunological characteristics of these subtypes are not fully understood. In this study, we investigated the immune landscape of NSCLC tissues in molecular subtypes using a multi-omics dataset, including tumor-infiltrating leukocytes (TILs) analyzed using flow cytometry, RNA sequences, whole exome sequences, metabolomic analysis, and clinicopathologic findings. In the PI subtype, the number of TILs increased and the immune response in the tumor microenvironment (TME) was activated, as indicated by high levels of tertiary lymphoid structures, and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. Glucose transporter 1 (GLUT1) expression levels were upregulated and lactate accumulated in the TME of the PP subtype. This could lead to the formation of an immunosuppressive TME, including the inactivation of antigen-presenting cells. The TRU subtype had low biological malignancy and "cold" tumor-immune phenotypes. Squamous cell carcinoma (LUSQ) did not show distinct immunological characteristics in its respective subtypes. Elucidation of the immune characteristics of molecular subtypes could lead to the development of personalized immune therapy for lung cancer. Immune checkpoint inhibitors could be an effective treatment for the PI subtype. Glycolysis is a potential target for converting an immunosuppressive TME into an antitumorigenic TME in the PP subtype.

Neutrophil-to-lymphocyte ratio is a prognostic factor reflecting immune condition of tumor microenvironment in squamous cell lung cancer.

Inflammatory factors in the peripheral blood, such as the C-reactive protein level and neutrophil-to-lymphocyte ratio (NLR), are prognostic markers in multiple types of cancer, including non-small cell lung cancer (NSCLC). However, the association between inflammatory factors and prognosis based on histological types has not been adequately reported. In addition, the relationship between these factors and the immune condition of the tumor microenvironment (TME) is unclear. In this single center, retrospective study, we first investigated the relationship between preoperative inflammatory markers and clinical outcomes in 176 patients with NSCLC who underwent surgery. Lung adenocarcinoma (LUAD) showed no significant prognostic marker, whereas for lung squamous cell carcinoma (LUSC), a multivariate analysis showed that a high NLR was significantly associated with postoperative recurrence. In LUSC patients, the median time of postoperative recurrence-free survival in patients with a low NLR was longer than that in patients with a high NLR. We then compared the tumor-infiltrating lymphocyte (TIL) profile with inflammatory markers in peripheral blood and found that the NLR was negatively correlated with the frequencies of T cells and B cells in LUSC tissues. Thus, the NLR is a useful predictive biomarker for postoperative recurrence and may reflect the immune condition of the TME in LUSC.

Fibroblast inhibition by tocilizumab enabled gemcitabine/nab-paclitaxel rechallenge for pancreatic cancer.

Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway inhibition may overcome chemoresistance of metastatic pancreatic cancer (MPC). We sought to determine the safety and recommended dose of tocilizumab (TCZ), an IL-6 receptor monoclonal antibody, and biological correlates of tumor shrinkage in patients with gemcitabine (GEM)/nanoparticle albumin-bound paclitaxel (nab-PTX)-refractory MPC. This phase 1 study enrolled 10 patients with MPC who had progressed after GEM/nab-PTX. Patients initially received TCZ 8 mg/kg on Day 1 and nab-PTX 100 mg/m2 + GEM 750 mg/m2 on Days 2, 9, and 16. Before and at the end of Cycle 1, biopsy of liver metastases was performed 3-5 h after levofloxacin (LVFX) administration to measure LVFX infiltration into tumor tissue. No dose-limited toxicities occurred, and the recommended dosage of TCZ was determined to be 8 mg/kg. Treatment-emergent adverse events occurred in 80% of patients, of which decreased neutrophil count was the most common. Tumor reduction during Cycle 1 was observed in four patients, who were defined as responders. In paired-biopsy samples, responder-related biological activities were an increase of cleaved PARP expression of tumor nuclei (p = 0.01), a decrease of proliferative cancer-associated fibroblasts (CAFs) (p = 0.08), and an increase of LVFX infiltration in the tumor (p = 0.04). A decrease of phosphorylated STAT3 expression (p = 0.02) favored an increase in LVFX infiltration. In conclusion, TCZ + GEM/nab-PTX-rechallenge had a manageable safety profile and showed preliminary activity via inhibition of CAF and improved intratumoral drug infiltration in MPC.

Data-driven categorization of postoperative delirium symptoms using unsupervised machine learning.

Background: Phenotyping analysis that includes time course is useful for understanding the mechanisms and clinical management of postoperative delirium. However, postoperative delirium has not been fully phenotyped. Hypothesis-free categorization of heterogeneous symptoms may be useful for understanding the mechanisms underlying delirium, although evidence is currently lacking. Therefore, we aimed to explore the phenotypes of postoperative delirium following invasive cancer surgery using a data-driven approach with minimal prior knowledge. Methods: We recruited patients who underwent elective invasive cancer resection. After surgery, participants completed 5 consecutive days of delirium assessments using the Delirium Rating Scale-Revised-98 (DRS-R-98) severity scale. We categorized 65 (13 questionnaire items/day × 5 days) dimensional DRS-R-98 scores using unsupervised machine learning (K-means clustering) to derive a small set of grouped features representing distinct symptoms across all participants. We then reapplied K-means clustering to this set of grouped features to delineate multiple clusters of delirium symptoms. Results: Participants were 286 patients, of whom 91 developed delirium defined according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria. Following the first K-means clustering, we derived four grouped symptom features: (1) mixed motor, (2) cognitive and higher-order thinking domain with perceptual disturbance and thought content abnormalities, (3) acute and temporal response, and (4) sleep-wake cycle disturbance. Subsequent K-means clustering permitted classification of participants into seven subgroups: (i) cognitive and higher-order thinking domain dominant delirium, (ii) prolonged delirium, (iii) acute and brief delirium, (iv) subsyndromal delirium-enriched, (v) subsyndromal delirium-enriched with insomnia, (vi) insomnia, and (vii) fit. Conclusion: We found that patients who have undergone invasive cancer resection can be delineated using unsupervised machine learning into three delirium clusters, two subsyndromal delirium clusters, and an insomnia cluster. Validation of clusters and research into the pathophysiology underlying each cluster will help to elucidate the mechanisms of postoperative delirium after invasive cancer surgery.

Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and Genetic Alterations.

Resistance to immune checkpoint blockade remains challenging in patients with non-small cell lung cancer (NSCLC). Tumor-infiltrating leukocyte (TIL) quantity, composition, and activation status profoundly influence responsiveness to cancer immunotherapy. This study examined the immune landscape in the NSCLC tumor microenvironment by analyzing TIL profiles of 281 fresh resected NSCLC tissues. Unsupervised clustering based on numbers and percentages of 30 TIL types classified adenocarcinoma (LUAD) and squamous cell carcinoma (LUSQ) into the cold, myeloid cell-dominant, and CD8+ T cell-dominant subtypes. These were significantly correlated with patient prognosis; the myeloid cell subtype had worse outcomes than the others. Integrated genomic and transcriptomic analyses, including RNA sequencing, whole-exome sequencing, T-cell receptor repertoire, and metabolomics of tumor tissue, revealed that immune reaction-related signaling pathways were inactivated, while the glycolysis and K-ras signaling pathways activated in LUAD and LUSQ myeloid cell subtypes. Cases with ALK and ROS1 fusion genes were enriched in the LUAD myeloid subtype, and the frequency of TERT copy-number variations was higher in LUSQ myeloid subtype than in the others. These classifications of NSCLC based on TIL status may be useful for developing personalized immune therapies for NSCLC. Significance: The precise TIL profiling classified NSCLC into novel three immune subtypes that correlates with patient outcome, identifying subtype-specific molecular pathways and genomic alterations that should play important roles in constructing subtype-specific immune tumor microenvironments. These classifications of NSCLC based on TIL status are useful for developing personalized immune therapies for NSCLC.

Elucidation of the mechanisms underlying tumor aggravation by the activation of stress-related neurons in the paraventricular nucleus of the hypothalamus.

A growing body of evidence suggests that excess stress could aggravate tumor progression. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the adaptation to stress because the hypothalamic-pituitary-adrenal (HPA) axis can be activated by inducing the release of corticotropin-releasing hormone (CRH) from the PVN. In this study, we used pharmacogenetic techniques to investigate whether concomitant activation of CRHPVN neurons could directly contribute to tumor progression. Tumor growth was significantly promoted by repeated activation of CRHPVN neurons, which was followed by an increase in the plasma levels of corticosterone. Consistent with these results, chronic administration of glucocorticoids induced tumor progression. Under the concomitant activation of CRHPVN neurons, the number of cytotoxic CD8+ T cells in the tumor microenvironment was dramatically decreased, and the mRNA expression levels of hypoxia inducible factor 1 subunit α (HIF1α), glucocorticoid receptor (GR) and Tsc22d3 were upregulated in inhibitory lymphocytes, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Furthermore, the mRNA levels of various kinds of driver molecules related to tumor progression and tumor metastasis were prominently elevated in cancer cells by concomitant activation of CRHPVN neurons. These findings suggest that repeated activation of the PVN-CRHergic system may aggravate tumor growth through a central-peripheral-associated tumor immune system.

ß-Catenin-activated inflammatory hepatocellular adenoma with pigmentation and atypical features: a case report.

Hepatocellular adenomas are rare diseases, defined as benign liver neoplasms composed of cells with hepatocellular differentiation. Differential diagnosis of hepatocellular adenoma from other lesions, including focal nodular hyperplasia and hepatocellular carcinoma, is crucial to determine treatment strategy. We describe a case of ß-catenin-activated inflammatory hepatocellular adenoma with malignant transformation. A 50-year-old man with a suspected liver tumor, based on abdominal ultrasonography findings, was referred to our hospital. Contrast-enhanced computed tomography and magnetic resonance imaging revealed a liver tumor in S2 which was enhanced in the arterial phase to the delayed phase. Based on diagnostic imaging findings, hepatocellular adenoma or focal nodular hyperplasia was suspected. We considered the possibility of malignant potential because of the enlargement of the lesion. Thus, we performed a laparoscopic hepatectomy. Histological examination showed pigment deposition in the hepatocytes, which was determined to be lipofuscin. Mild nuclear swelling and atypia in the tumor area indicated nodular growth. Based on the histological and immunohistochemical findings, the diagnosis was ꞵ-catenin-activated inflammatory hepatocellular adenoma with atypical features. The imaging features of hepatocellular adenoma and focal nodular hyperplasia are similar, but if the tumor tends to grow, surgical treatment should be performed because of the possibility of malignant hepatocellular adenoma.

Time course of serum cytokine level changes within 72 h after onset in children with acute encephalopathy and febrile seizures.

BACKGROUND: Cytokine levels have been measured in acute encephalopathy (AE) to determine its pathology or as a diagnostic biomarker to distinguish it from febrile seizures (FS); however, the dynamics of cytokine level changes have not yet been fully captured in these two neurological manifestations. Thus, we aimed to explore the time course of serum cytokine level changes within 72 h after onset in AE and FS. METHODS: We retrospectively measured cytokine level in residual serum samples at multiple timepoints in seven children whose final diagnoses were AE or FS. RESULTS: The levels of 13 cytokines appeared to increase immediately after onset and peaked within 12-24 h after onset: interleukin (IL)-1ß, IL-4 IL-5, IL-6, IL-8, IL-10, IL-17, eotaxin, fibroblast growth factor, granulocyte colony-stimulating factor, interferon gamma, interferon-inducible protein-10, and macrophage chemoattractant protein-1. There were no dynamic changes in the levels of three cytokines (IL-1 receptor agonist, macrophage inflammatory protein-1α, and platelet-derived growth factor-bb) 72 h after onset. Levels of some cytokines decreased to around control levels within 48 h after onset: IL-1ß, IL-4, IL-5, IL-17, fibroblast growth factor, and interferon gamma. The levels of most cytokines appeared to be higher in AE, especially in hemorrhagic shock encephalopathy syndrome, than in FS. CONCLUSIONS: Cytokine levels in both AE and FS change dynamically, such as the levels of several cytokines increased within a few hours after onset and decreased at 12-24 h after onset. Therefore, it will be desirable to make clinical decisions regarding the administration of anti-inflammatory therapy in 24 h after onset in AE.

Machine learning predicts blood lactate levels in children after cardiac surgery in paediatric ICU.

BACKGROUND: Although serum lactate levels are widely accepted markers of haemodynamic instability, an alternative method to evaluate haemodynamic stability/instability continuously and non-invasively may assist in improving the standard of patient care. We hypothesise that blood lactate in paediatric ICU patients can be predicted using machine learning applied to arterial waveforms and perioperative characteristics. METHODS: Forty-eight post-operative children, median age 4 months (2.9-11.8 interquartile range), mean baseline heart rate of 131 beats per minute (range 33-197), mean lactate level at admission of 22.3 mg/dL (range 6.3-71.1), were included. Morphological arterial waveform characteristics were acquired and analysed. Predicting lactate levels was accomplished using regression-based supervised learning algorithms, evaluated with hold-out cross-validation, including, basing prediction on the currently acquired physiological measurements along with those acquired at admission, as well as adding the most recent lactate measurement and the time since that measurement as prediction parameters. Algorithms were assessed with mean absolute error, the average of the absolute differences between actual and predicted lactate concentrations. Low values represent superior model performance. RESULTS: The best performing algorithm was the tuned random forest, which yielded a mean absolute error of 3.38 mg/dL when predicting blood lactate with updated ground truth from the most recent blood draw. CONCLUSIONS: The random forest is capable of predicting serum lactate levels by analysing perioperative variables, including the arterial pressure waveform. Thus, machine learning can predict patient blood lactate levels, a proxy for haemodynamic instability, non-invasively, continuously and with accuracy that may demonstrate clinical utility.

Nucleic acid-triggered tumoral immunity propagates pH-selective therapeutic antibodies through tumor-driven epitope spreading.

Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer-derived antibodies exhibited acidic pH-selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.

Conversion surgery following gemcitabine plus cisplatin therapy for initially unresectable gallbladder cancer with peritoneal carcinomatosis: a case report.

BACKGROUND: Conversion surgery, which is defined as chemotherapy or chemoradiotherapy followed by radical surgery, may improve survival of patients with initially unresectable advanced biliary tract cancer, including gallbladder cancer. However, there are few reports on conversion surgery for advanced gallbladder cancer. CASE PRESENTATION: A 69-year-old woman was referred to our hospital with initially unresectable gallbladder cancer with peritoneal carcinomatosis. She underwent gemcitabine plus cisplatin therapy for 9 months. Extended cholecystectomy, resection of the extrahepatic bile duct with regional lymph node dissection, and total omentectomy were then performed as conversion surgery. The patient has survived without recurrence for 19 months postoperatively (31 months after the initial diagnosis) while continuing chemotherapy. CONCLUSIONS: This case suggests that conversion surgery for advanced gallbladder cancer is effective and may be curative for locally advanced disease and distant metastasis such as peritoneal carcinomatosis.

Imatinib Mesylate Exerted Antitumor Effect by Promoting Infiltration of Effector T Cells in Tumor.

Imatinib mesylate is a potent tyrosine kinase inhibitor that may induce immunological effects, such as inhibition of immune suppressive cells; but, how it modulates the immune system remains to be completely elucidated. In this study, we showed that cell proliferation of CT26 colon cancer and Lewis lung carcinoma (3LL) lung cancer cells was not inhibited by imatinib in vitro, although its administration significantly suppressed the growth of CT26, but not 3LL, subcutaneous tumors, and prolonged survival in CT26 tumor-bearing mice. Further, we examined the expression of immune cell-related molecules in the tumors to elucidate the differences in imatinib-mediated antitumor effects between CT26 and 3LL tumors. The nCounter assay showed that the expression of CD8 and CD8+ T cell-recruiting chemokine genes was significantly elevated in imatinib-treated CT26 tumors than that in control tumors; however, the gene expression remained unchanged in imatinib-treated or control 3LL tumors. Furthermore, frequency of interferon-γ+ (IFN-γ+) CD8+ T cells was increased in imatinib-treated CT26 tumors than control tumors, indicating induction of antitumor immunity by imatinib. The analysis indicates that imatinib promotes infiltration of effector T cells in tumors by upregulating expression of cytokines that recruit CD8+ T cells in the tumor microenvironment, which may lead to a strong antitumor effect.

Closed-PICU perioperative management of congenital tracheal stenosis.

BACKGROUND: Perioperative management of congenital tracheal stenosis (CTS) is challenging. In the present study, compared the effect of closed-pediatric intensive care unit (PICU) perioperative management by pediatric intensivists and open-PICU management by surgeons. Outcomes in terms of ventilator-free days (VFD) and length of postoperative PICU stay in children with CTS were evaluated. METHODS: This retrospective cohort study was conducted in a PICU in Japan. Children with CTS who underwent slide tracheoplasty were grouped according to whether they were perioperatively managed in an open (January 2015 to April 2016) or a closed (May 2016 to August 2019) PICU. Data were extracted from patients' medical records. RESULTS: In total, 13 and 38 patients were included in the open- and closed-PICU groups, respectively. Compared to the open-PICU group, the closed-PICU group had shorter duration of muscle relaxant administration (median 4 vs 5 days; P < 0.001), earlier enteral nutrition (34/38 [90%] vs 1/13 [8%]; P < 0.001), more 28-day VFD (median 21 vs 20 days; P = 0.04), and shorter duration of postoperative PICU stay (median 16 vs 36 days; P = 0.002), but mortality did not differ significantly between the two groups (0/38 [0%] vs 1/13 [8%]; P = 0.25). CONCLUSIONS: Closed-PICU perioperative management with pediatric intensivists' participation significantly increased 28-day VFD and reduced the length of postoperative PICU stay in patients with congenital tracheal stenosis.

Development of an in vitro carcinogenesis model of human papillomavirus-induced cervical adenocarcinoma.

Cervical adenocarcinoma (ADC) is the second most common pathological subtype of cervical cancer after squamous cell carcinoma. It accounts for approximately 20% of cervical cancers, and the incidence has increased in the past few decades, particularly among young patients. The persistent infection of high-risk human papillomavirus (HPV) is responsible for most cervical ADC. However, almost all available in vitro models are designed to study the carcinogenesis of cervical squamous cell carcinoma. To gain better insights into molecular background of ADC, we aimed to establish an in vitro carcinogenesis model of ADC. We previously reported the establishment of an in vitro model for cervical squamous cell carcinoma by introducing defined viral and cellular oncogenes, HPV16 E6 and E7, c-MYC, and activated RAS to human cervical keratinocytes. In this study, the expression of potential lineage-specifying factors and/or SMAD4 reduction was introduced in addition to the defined four oncogenes to direct carcinogenesis toward ADC. The cell properties associated with the cell lineage were analyzed in monolayer and organoid cultures and the tumors in mouse xenografts. In the cells expressing Forkhead box A2 (FOXA2), apparent changes in cell properties were observed, such as elevated expression of columnar cell markers and decreased expression of squamous cell markers. Strikingly, the histopathology of tumors expressing FOXA2 resembled cervical ADC, proposing that FOXA2 plays a vital role in dictating the histopathology of cervical cancers.

Stemness and immune evasion conferred by the TDO2-AHR pathway are associated with liver metastasis of colon cancer.

The aryl hydrocarbon receptor (AHR) pathway modulates the immune system in response to kynurenine, an endogenous tryptophan metabolite. IDO1 and TDO2 catalyze kynurenine production, which promotes cancer progression by compromising host immunosurveillance. However, it is unclear whether the AHR activation regulates the malignant traits of cancer such as metastatic capability or cancer stemness. Here, we carried out systematic analyses of metabolites in patient-derived colorectal cancer spheroids and identified high levels of kynurenine and TDO2 that were positively associated with liver metastasis. In a mouse colon cancer model, TDO2 expression substantially enhanced liver metastasis, induced AHR-mediated PD-L1 transactivation, and dampened immune responses; these changes were all abolished by PD-L1 knockout. In patient-derived cancer spheroids, TDO2 or AHR activity was required for not only the expression of PD-L1, but also for cancer stem cell (CSC)-related characteristics and Wnt signaling. TDO2 was coexpressed with both PD-L1 and nuclear ß-catenin in colon xenograft tumors, and the coexpression of TDO2 and PD-L1 was observed in clinical colon cancer specimens. Thus, our data indicate that the activation of the TDO2-kynurenine-AHR pathway facilitates liver metastasis of colon cancer via PD-L1-mediated immune evasion and maintenance of stemness.