CXCR6 Inhibits Hepatocarcinogenesis by Promoting Natural Killer T- and CD4+ T-Cell–Dependent Control of Senescence

Mossanen, Jana C.; Kohlhepp, Marlene; Wehr, Alexander; Krenkel, Oliver; Liepelt, Anke; Roeth, Anjali A.; Möckel, Diana; Heymann, Felix; Lammers, Twan; Gaßler, Nikolaus; Hermann, Juliane; Jankowski, Joachim; Neumann, Ulf; Luedde, Tom; Trautwein, Christian; Tacke, Frank

doi:10.1053/j.gastro.2019.01.247

Cited by 91 publications

(74 citation statements)

References 43 publications

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“…While the role of NK cells as antifibrotic cells that remove activated HSCs and produce IFN-γ has been clearly delineated, NKT cells have been shown to both produce profibrotic cytokines (IL-4 and IL-13) and to have an antifibrotic role in removing activated HSCs [ 61 ]. After induction of liver injury in mice, NKT cell accumulation is an early event that promotes sustained tissue inflammation [ 82 ]; this inflammatory activity, however, also helps to recognize and remove senescent hepatocytes as a tumor-preventive immune surveillance mechanism [ 83 ]. An accumulation and activation of intrahepatic CD4+ T cells, CD8+ T cells, regulatory T cells and NKT cells has been observed in NASH models of mice fed with a MCD-diet.…”

Section: Fibrosis and Cirrhosismentioning

confidence: 99%

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

Lurje

Hammerich

Tacke

2020

IJMS

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Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC–T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation.

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Section: Fibrosis and Cirrhosismentioning

confidence: 99%

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

Lurje

Hammerich

Tacke

2020

IJMS

Self Cite

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“…188 Accumulated hepatic NKT cells were found to show an activated phenotype as effectormemory CD44 hi CD62L low cells with higher levels of CD69 expression and increased production of IFN-γ upon antigen stimulation, which mediated inhibition of both primary and metastatic liver tumors. 189,190 CXCL16 derived from LSECs regulated CXCR6 + NKT cell accumulation, making up the majority (~75%) of hepatic CXCR6 + cells, which was controlled by primaryto-secondary bile acid conversion mediated by the gut microbiome as a messenger regulating CXCL16 levels. 190 In mice, depletion of commensal bacteria with antibiotics led to primary bile acid-induced CXCL16 and reduced secondary bile acidinhibited CXCL16, resulting in the upregulation of CXCL16 in LSECs that accumulated NKT cells into the liver.…”

Section: Viral Infectionmentioning

confidence: 99%

“…62 Injection of α-Galcer activates NKT cells and increases their removal of senescent hepatocytes, which prevents hepatocarcinogenesis. 189 Targeting the LIGIT-LTβ R interaction or hedgehog pathway prevents cross-talk between NKT cells and hepatocytes, efficiently inhibiting the development of liver damage NASH and HCC. 147,149 Treatment with tazarotene, a kind of RAR-γ agonist, inhibits cell proliferation and cytokine production of iNKT cells, which significantly reduces liver steatosis and fibrosis.…”

Section: Cytokines or Immune Stimulatorsmentioning

confidence: 99%

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

Chen

Tian

2020

Cell Mol Immunol

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The liver is a lymphoid organ with unique immunological properties, particularly, its predominant innate immune system. The balance between immune tolerance and immune activity is critical to liver physiological functions and is responsible for the sensitivity of this organ to numerous diseases, including hepatotropic virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, autoimmune liver disease, and liver cancer, which are major health problems globally. In the past decade, with the discovery of liver-resident natural killer cells, the importance of innate lymphocytes with tissue residency has gradually become the focus of research. In this review, we address the current knowledge regarding hepatic innate lymphocytes with unique characteristics, including NK cells, ILC1/2/3s, NKT cells, γδ T cells, and MAIT cells, and their potential roles in liver homeostasis maintenance and the progression of liver diseases and cancer. A better understanding of the immunopathogenesis of hepatic innate lymphocytes will be helpful for proposing effective treatments for liver diseases and cancer.

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“…However, CXCR6 has been shown to predict poor prognosis in gastric cancer, breast cancer, prostate cancer and bladder cancer [46][47][48][49]. On contrary, CXCR6 was also found to be necessary for promoting NKT and CD4 T cells to remove senescent hepatocytes to prevent hepatocarcinogenesis [50], which might indicate a similar mechanism in MIBC. Interleukin-2 (IL-2) was one of the rst FDA-approved immunotherapy drugs for melanoma and renal cell cancer.…”

Section: Discussionmentioning

confidence: 98%

Machine Learning Prediction Models Based on Hub Genes Related to Immune Phenotypes in Muscle-Invasive Bladder Cancer Treated With Immune Checkpoint Blockade

Chen

Wang

et al. 2020

Preprint

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Background: Bladder cancer is one of the most frequent cancer in the world. Muscle-invasive bladder cancer (MIBC) is a more aggressive subtype with higher morbidity and mortality. ICB therapy has shown potential for treating MIBC, but is limited due to the lack of predictive biomarkers.Methods: 1601 MIBC transcriptomic profiles were obtained from 10 datasets. Unsupervised clustering of immune phenotypes in MIBC were performed based on immune-related signature genes. We analyzed the characteristics including immune microenvironments, metabolic pathways, and survival rates in different phenotypes. Multi-omic analysis and WGCNA were performed to identify hub genes distinguishing phenotypes related to prognosis. A model was established and CART was employed to predict the response of patients treated with ICB.Results: Of various immune phenotypes, cluster 3C was the most “inflamed” subcluster with the best prognosis, while cluster 1A was associated with “non-inflammation” and worse prognosis. WGCNA analysis identified 5 hub genes related to the survival rate of patients, IFNG, CXCR6, IL2RB, LCK, and PSMB10, which were utilized for prognostic score model and decision tree analysis. The areas under the curve (AUC) of the ROC curves predicting 5-year endpoint generated from the risk-based prediction model were 0.652. The mean accuracy, sensitivity, and specificity of CART for predicting stable disease/progressive disease were 70.1%, 70.0% and 71.7%.Conclusions: The 5 hub genes and generated models showed the potential for predicting the prognosis for patients receiving ICB therapy. The molecular mechanisms regulating the expression of the hub genes require further studies in the future.

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CXCR6 Inhibits Hepatocarcinogenesis by Promoting Natural Killer T- and CD4+ T-Cell–Dependent Control of Senescence

Cited by 91 publications

References 43 publications

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

Machine Learning Prediction Models Based on Hub Genes Related to Immune Phenotypes in Muscle-Invasive Bladder Cancer Treated With Immune Checkpoint Blockade

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