Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes
Autor: | Xiao-Fan Wang, Bin Yang, Wenhao Qin, Anna Mae Diehl, Gregory A. Michelotti, Qi-Jing Li, Geoffrey J. Markowitz, Rui Chen, Jianhua Sui, Zheng Zhang, Jing Fu, Fu-Sheng Wang, Hongyang Wang, Pengyuan Yang |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cancer Research Pathology medicine.medical_specialty Carcinoma Hepatocellular medicine.medical_treatment Inflammation Biology Article Mice 03 medical and health sciences Lymphocytes Tumor-Infiltrating medicine Carcinoma Animals Humans Mice Knockout Receptors Interleukin-18 Tumor-infiltrating lymphocytes Liver Neoplasms Interleukin-18 Cancer Prognosis medicine.disease digestive system diseases 030104 developmental biology Cytokine Oncology Hepatocellular carcinoma Interleukin 18 medicine.symptom Signal transduction Signal Transduction |
Zdroj: | Cancer Research. 76:2394-2405 |
ISSN: | 1538-7445 0008-5472 |
Popis: | Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma. High levels of inflammatory cytokine IL18 in the circulation of patients with hepatocellular carcinoma correlates with poor prognosis. However, conflicting results have been reported for IL18 in hepatocellular carcinoma development and progression. In this study, we used tissue specimens from hepatocellular carcinoma patients and clinically relevant mouse models of hepatocellular carcinoma to evaluate IL18 expression and function. In a mouse model of liver fibrosis that recapitulates a tumor-promoting microenvironment, global deletion of the IL18 receptor IL18R1 enhanced tumor growth and burden. Similarly, in a carcinogen-induced model of liver tumorigenesis, IL18R1 deletion increased tumor burden. Mechanistically, we found that IL18 exerted inflammation-dependent tumor-suppressive effects largely by promoting the differentiation, activity, and survival of tumor-infiltrating T cells. Finally, differences in the expression of IL18 in tumor tissue versus nontumor tissue were more predictive of patient outcome than overall tissue expression. Taken together, our findings resolve a long-standing contradiction regarding a tumor-suppressive role for IL18 in established hepatocellular carcinoma and provide a mechanistic explanation for the complex relationship between its expression pattern and hepatocellular carcinoma prognosis. Cancer Res; 76(8); 2394–405. ©2016 AACR. |
Databáze: | OpenAIRE |
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