Cargando…

TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration

BACKGROUND: Numerous cancer types present the aberrant TANK-binding kinase 1 (TBK1) expression, which plays an important role in driving inflammation and innate immunity. However, the prognostic role of TBK1 and its relationship with immune cell infiltration in hepatocellular carcinoma (HCC) remain...

Descripción completa

Detalles Bibliográficos
Autores principales: Jiang, Yuchuan, Chen, Siliang, Li, Qiang, Liang, Junjie, Lin, Weida, Li, Jinying, Liu, Zhilong, Wen, Mingbo, Cao, Mingrong, Hong, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930497/
https://www.ncbi.nlm.nih.gov/pubmed/33679751
http://dx.doi.org/10.3389/fimmu.2021.612139
_version_ 1783660112863297536
author Jiang, Yuchuan
Chen, Siliang
Li, Qiang
Liang, Junjie
Lin, Weida
Li, Jinying
Liu, Zhilong
Wen, Mingbo
Cao, Mingrong
Hong, Jian
author_facet Jiang, Yuchuan
Chen, Siliang
Li, Qiang
Liang, Junjie
Lin, Weida
Li, Jinying
Liu, Zhilong
Wen, Mingbo
Cao, Mingrong
Hong, Jian
author_sort Jiang, Yuchuan
collection PubMed
description BACKGROUND: Numerous cancer types present the aberrant TANK-binding kinase 1 (TBK1) expression, which plays an important role in driving inflammation and innate immunity. However, the prognostic role of TBK1 and its relationship with immune cell infiltration in hepatocellular carcinoma (HCC) remain unclear. METHODS: The expression and prognostic value of TBK1 was analyzed by Tumor Immune Estimation Resource (TIMER), Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and further confirmed in the present cohort of patients with HCC. The association between TBK1 and HCC immune infiltrates, and its potential mechanism were investigated via analyses of the Tumor Immune Estimation Resource, tumor-immune system interactions database (TISIDB), CIBERSORT, STRING, and Metascape. The effect of TBK1 on immune infiltrates and the therapeutic value of targeting TBK1 were further investigated in a HCC mouse model by treatment with a TBK1 antagonist. RESULTS: The level of TBK1 expression in HCC was higher than that measured in normal tissues, and associated with poorer overall survival (GEPIA: hazard ratio [HR]=1.80, P=0.038; Kaplan–Meier plotter: HR=1.87, P<0.001; CPTAC: HR=2.23, P=0.007; Our cohort: HR=2.92, P=0.002). In addition, high TBK1 expression was found in HCC with advanced TNM stage and identified as an independent poor prognostic factor for overall survival among patients with HCC. In terms of immune infiltration, tumor tissues from HCC patients with high TBK1 expression had a low proportion of CD8(+) T cells, and TBK1 expression did not show prognostic value in HCC patients with enriched CD8+ T cells. Furthermore, TBK1 expression was positively correlated with the markers of T cell exhaustion and immunosuppressive cells in the HCC microenvironment. Mechanistically, the promotion of HCC immunosuppression by TBK1 was involved in the regulation of inflammatory cytokines. In vivo experiments revealed that treatment with a TBK1 antagonist delayed HCC growth by increasing the number of tumor-infiltrating CD8+ T cells. CONCLUSIONS: The up-regulated expression of TBK1 may be useful in predicting poor prognosis of patients with HCC. In addition, TBK1, which promotes the HCC immunosuppressive microenvironment, may be a potential immunotherapeutic target for patients with HCC.
format Online
Article
Text
id pubmed-7930497
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-79304972021-03-05 TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration Jiang, Yuchuan Chen, Siliang Li, Qiang Liang, Junjie Lin, Weida Li, Jinying Liu, Zhilong Wen, Mingbo Cao, Mingrong Hong, Jian Front Immunol Immunology BACKGROUND: Numerous cancer types present the aberrant TANK-binding kinase 1 (TBK1) expression, which plays an important role in driving inflammation and innate immunity. However, the prognostic role of TBK1 and its relationship with immune cell infiltration in hepatocellular carcinoma (HCC) remain unclear. METHODS: The expression and prognostic value of TBK1 was analyzed by Tumor Immune Estimation Resource (TIMER), Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and further confirmed in the present cohort of patients with HCC. The association between TBK1 and HCC immune infiltrates, and its potential mechanism were investigated via analyses of the Tumor Immune Estimation Resource, tumor-immune system interactions database (TISIDB), CIBERSORT, STRING, and Metascape. The effect of TBK1 on immune infiltrates and the therapeutic value of targeting TBK1 were further investigated in a HCC mouse model by treatment with a TBK1 antagonist. RESULTS: The level of TBK1 expression in HCC was higher than that measured in normal tissues, and associated with poorer overall survival (GEPIA: hazard ratio [HR]=1.80, P=0.038; Kaplan–Meier plotter: HR=1.87, P<0.001; CPTAC: HR=2.23, P=0.007; Our cohort: HR=2.92, P=0.002). In addition, high TBK1 expression was found in HCC with advanced TNM stage and identified as an independent poor prognostic factor for overall survival among patients with HCC. In terms of immune infiltration, tumor tissues from HCC patients with high TBK1 expression had a low proportion of CD8(+) T cells, and TBK1 expression did not show prognostic value in HCC patients with enriched CD8+ T cells. Furthermore, TBK1 expression was positively correlated with the markers of T cell exhaustion and immunosuppressive cells in the HCC microenvironment. Mechanistically, the promotion of HCC immunosuppression by TBK1 was involved in the regulation of inflammatory cytokines. In vivo experiments revealed that treatment with a TBK1 antagonist delayed HCC growth by increasing the number of tumor-infiltrating CD8+ T cells. CONCLUSIONS: The up-regulated expression of TBK1 may be useful in predicting poor prognosis of patients with HCC. In addition, TBK1, which promotes the HCC immunosuppressive microenvironment, may be a potential immunotherapeutic target for patients with HCC. Frontiers Media S.A. 2021-02-18 /pmc/articles/PMC7930497/ /pubmed/33679751 http://dx.doi.org/10.3389/fimmu.2021.612139 Text en Copyright © 2021 Jiang, Chen, Li, Liang, Lin, Li, Liu, Wen, Cao and Hong http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Jiang, Yuchuan
Chen, Siliang
Li, Qiang
Liang, Junjie
Lin, Weida
Li, Jinying
Liu, Zhilong
Wen, Mingbo
Cao, Mingrong
Hong, Jian
TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration
title TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration
title_full TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration
title_fullStr TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration
title_full_unstemmed TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration
title_short TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration
title_sort tank-binding kinase 1 (tbk1) serves as a potential target for hepatocellular carcinoma by enhancing tumor immune infiltration
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930497/
https://www.ncbi.nlm.nih.gov/pubmed/33679751
http://dx.doi.org/10.3389/fimmu.2021.612139
work_keys_str_mv AT jiangyuchuan tankbindingkinase1tbk1servesasapotentialtargetforhepatocellularcarcinomabyenhancingtumorimmuneinfiltration
AT chensiliang tankbindingkinase1tbk1servesasapotentialtargetforhepatocellularcarcinomabyenhancingtumorimmuneinfiltration
AT liqiang tankbindingkinase1tbk1servesasapotentialtargetforhepatocellularcarcinomabyenhancingtumorimmuneinfiltration
AT liangjunjie tankbindingkinase1tbk1servesasapotentialtargetforhepatocellularcarcinomabyenhancingtumorimmuneinfiltration
AT linweida tankbindingkinase1tbk1servesasapotentialtargetforhepatocellularcarcinomabyenhancingtumorimmuneinfiltration
AT lijinying tankbindingkinase1tbk1servesasapotentialtargetforhepatocellularcarcinomabyenhancingtumorimmuneinfiltration
AT liuzhilong tankbindingkinase1tbk1servesasapotentialtargetforhepatocellularcarcinomabyenhancingtumorimmuneinfiltration
AT wenmingbo tankbindingkinase1tbk1servesasapotentialtargetforhepatocellularcarcinomabyenhancingtumorimmuneinfiltration
AT caomingrong tankbindingkinase1tbk1servesasapotentialtargetforhepatocellularcarcinomabyenhancingtumorimmuneinfiltration
AT hongjian tankbindingkinase1tbk1servesasapotentialtargetforhepatocellularcarcinomabyenhancingtumorimmuneinfiltration