TLR3 Expression is a Potential Prognosis Biomarker and Shapes the Immune-Active Tumor Microenvironment in Esophageal Squamous Cell Carcinoma.
TLR3 Expression is a Potential Prognosis Biomarker and Shapes the Immune-Active Tumor Microenvironment in Esophageal Squamous Cell Carcinoma.
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TLR3 表达是一种潜在的预后生物标志物，可塑造食管鳞状细胞癌的免疫活性肿瘤微环境
DOI：
10.2147/jir.s348786
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发表时间：
2022
影响因子：
4.5
通讯作者：
Su M
中科院分区：
文献类型：
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作者：
Su R;Cai L;Xiong P;Liu Z;Chen S;Liu X;Lin R;Lei Z;Tian D;Su M
背景Toll样受体3(TLR3)不仅在先天免疫和炎症反应中发挥重要作用，而且在抗癌免疫中也发挥重要作用。然而，TLR3在ESCC中的临床病理结果仍然不明确。方法应用免疫组织化学方法检测137例食管鳞癌患者(包括37例不同早期病变的配对食管鳞癌组织)中TLR3的表达及其对预后的影响。此外，我们从癌症基因组图谱(TCGA)下载了ESCC RNA-seq数据集(包括表型和生存数据)。评估TLR3与预后、生物学特性和免疫浸润的关系，以验证我们组织标本的免疫组织化学结果，探索影响预后的可能机制，并预测免疫治疗的敏感性。结果TLR3蛋白在不同程度的细胞异型性中的表达呈递增趋势，从正常、单纯增生、上皮内瘤变到食管鳞癌(P<；0.0083)。TLR3蛋白与炎症程度呈正相关(Rho=0.341，P<；0.001)。TLR3mRNA的表达显著高于癌旁正常组织(P<；0.001)。COX回归分析显示，TLR3蛋白和mRNA的高表达预示着TCGA的良好预后，尤其是在晚期ESCC患者(TNM分期III和IV期)。TLR3的过表达导致免疫活性细胞的募集，包括细胞毒性淋巴细胞(CTL)、CD8+T细胞、NK细胞、树突状细胞和M1型巨噬细胞。TLR3的表达与与抗肿瘤免疫相关的促炎细胞因子和趋化因子相关。GSEA分析表明，TLR3表达上调可激活细胞凋亡途径。结论食管鳞癌患者TLR3高表达与预后好、免疫活性细胞浸润和细胞凋亡途径激活有关。TLR3在ESCC患者的免疫治疗和免疫应答预测中具有潜在的应用价值。
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.