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TLR3 Expression is a Potential Prognosis Biomarker and Shapes the Immune-Active Tumor Microenvironment in Esophageal Squamous Cell Carcinoma

BACKGROUND: Toll-like receptor 3 (TLR3) not only plays a crucial role in innate immune and inflammation but also in anti-cancer immunity. Nevertheless, the clinicopathological outcome of TLR3 in ESCC is still ambiguous. METHODS: Immunohistochemistry was performed to investigate TLR3 expression and i...

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Autores principales: Su, Ruibing, Cai, Lijun, Xiong, Pan, Liu, Zhiwei, Chen, Shaobin, Liu, Xi, Lin, Runhua, Lei, Zhijin, Tian, Dongping, Su, Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8896387/
https://www.ncbi.nlm.nih.gov/pubmed/35250293
http://dx.doi.org/10.2147/JIR.S348786
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author Su, Ruibing
Cai, Lijun
Xiong, Pan
Liu, Zhiwei
Chen, Shaobin
Liu, Xi
Lin, Runhua
Lei, Zhijin
Tian, Dongping
Su, Min
author_facet Su, Ruibing
Cai, Lijun
Xiong, Pan
Liu, Zhiwei
Chen, Shaobin
Liu, Xi
Lin, Runhua
Lei, Zhijin
Tian, Dongping
Su, Min
author_sort Su, Ruibing
collection PubMed
description BACKGROUND: Toll-like receptor 3 (TLR3) not only plays a crucial role in innate immune and inflammation but also in anti-cancer immunity. Nevertheless, the clinicopathological outcome of TLR3 in ESCC is still ambiguous. METHODS: Immunohistochemistry was performed to investigate TLR3 expression and its impact on survival in 137 ESCC patients (including paired esophageal tissues with different stages of early lesions from 37 patients). Furthermore, we downloaded ESCC RNA-seq datasets (including phenotype and survival data) from The Cancer Genome Atlas (TCGA). The relationship between TLR3 and prognosis, biological landscape, and immune infiltration was assessed to verify the immunohistochemical results of our tissue samples, explore the possible mechanism of prognostic outcomes, and predict the sensitivity of immunotherapy. RESULTS: TLR3 protein expression displayed an increasing trend in the progression through different grades of cellular atypia, from normal, esophageal simple hyperplasia (ESSH), intraepithelial neoplasia (IEN) to ESCC (P < 0.0083). TLR3 protein had a positive association with inflammation level (Rho = 0.341, P < 0.001). TLR3 mRNA expression was significantly higher in comparison to adjacent normal tissues (P < 0.001). Cox regression analysis indicated high TLR3 protein and mRNA expression conferred good prognosis in our samples and TCGA, especially for advanced ESCC patients (TNM stage III and IV). Overexpression of TLR3 resulted in an immune-active microenvironment via the recruitment of immune-active cells including cytotoxic lymphocytes (CTLs), CD8+ T cells, NK cells, dendritic cells, and M1-type macrophages. TLR3 expression was correlated with the pro-inflammatory cytokines and chemokines relating to anti-tumor immunity. Moreover, GSEA analysis indicated upregulated expression of TLR3 could activate the apoptotic pathway. CONCLUSION: High TLR3 expression in ESCC patients was associated with a more favorable prognosis, immune-active cell infiltration, and an activated apoptotic pathway. TLR3 has potential applications for immunotherapy and immune response prediction in patients with ESCC.
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spelling pubmed-88963872022-03-05 TLR3 Expression is a Potential Prognosis Biomarker and Shapes the Immune-Active Tumor Microenvironment in Esophageal Squamous Cell Carcinoma Su, Ruibing Cai, Lijun Xiong, Pan Liu, Zhiwei Chen, Shaobin Liu, Xi Lin, Runhua Lei, Zhijin Tian, Dongping Su, Min J Inflamm Res Original Research BACKGROUND: Toll-like receptor 3 (TLR3) not only plays a crucial role in innate immune and inflammation but also in anti-cancer immunity. Nevertheless, the clinicopathological outcome of TLR3 in ESCC is still ambiguous. METHODS: Immunohistochemistry was performed to investigate TLR3 expression and its impact on survival in 137 ESCC patients (including paired esophageal tissues with different stages of early lesions from 37 patients). Furthermore, we downloaded ESCC RNA-seq datasets (including phenotype and survival data) from The Cancer Genome Atlas (TCGA). The relationship between TLR3 and prognosis, biological landscape, and immune infiltration was assessed to verify the immunohistochemical results of our tissue samples, explore the possible mechanism of prognostic outcomes, and predict the sensitivity of immunotherapy. RESULTS: TLR3 protein expression displayed an increasing trend in the progression through different grades of cellular atypia, from normal, esophageal simple hyperplasia (ESSH), intraepithelial neoplasia (IEN) to ESCC (P < 0.0083). TLR3 protein had a positive association with inflammation level (Rho = 0.341, P < 0.001). TLR3 mRNA expression was significantly higher in comparison to adjacent normal tissues (P < 0.001). Cox regression analysis indicated high TLR3 protein and mRNA expression conferred good prognosis in our samples and TCGA, especially for advanced ESCC patients (TNM stage III and IV). Overexpression of TLR3 resulted in an immune-active microenvironment via the recruitment of immune-active cells including cytotoxic lymphocytes (CTLs), CD8+ T cells, NK cells, dendritic cells, and M1-type macrophages. TLR3 expression was correlated with the pro-inflammatory cytokines and chemokines relating to anti-tumor immunity. Moreover, GSEA analysis indicated upregulated expression of TLR3 could activate the apoptotic pathway. CONCLUSION: High TLR3 expression in ESCC patients was associated with a more favorable prognosis, immune-active cell infiltration, and an activated apoptotic pathway. TLR3 has potential applications for immunotherapy and immune response prediction in patients with ESCC. Dove 2022-02-28 /pmc/articles/PMC8896387/ /pubmed/35250293 http://dx.doi.org/10.2147/JIR.S348786 Text en © 2022 Su et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Su, Ruibing
Cai, Lijun
Xiong, Pan
Liu, Zhiwei
Chen, Shaobin
Liu, Xi
Lin, Runhua
Lei, Zhijin
Tian, Dongping
Su, Min
TLR3 Expression is a Potential Prognosis Biomarker and Shapes the Immune-Active Tumor Microenvironment in Esophageal Squamous Cell Carcinoma
title TLR3 Expression is a Potential Prognosis Biomarker and Shapes the Immune-Active Tumor Microenvironment in Esophageal Squamous Cell Carcinoma
title_full TLR3 Expression is a Potential Prognosis Biomarker and Shapes the Immune-Active Tumor Microenvironment in Esophageal Squamous Cell Carcinoma
title_fullStr TLR3 Expression is a Potential Prognosis Biomarker and Shapes the Immune-Active Tumor Microenvironment in Esophageal Squamous Cell Carcinoma
title_full_unstemmed TLR3 Expression is a Potential Prognosis Biomarker and Shapes the Immune-Active Tumor Microenvironment in Esophageal Squamous Cell Carcinoma
title_short TLR3 Expression is a Potential Prognosis Biomarker and Shapes the Immune-Active Tumor Microenvironment in Esophageal Squamous Cell Carcinoma
title_sort tlr3 expression is a potential prognosis biomarker and shapes the immune-active tumor microenvironment in esophageal squamous cell carcinoma
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8896387/
https://www.ncbi.nlm.nih.gov/pubmed/35250293
http://dx.doi.org/10.2147/JIR.S348786
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