Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Medical Genetics Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.
J Mol Histol. 2021 Jun;52(3):597-609. doi: 10.1007/s10735-021-09971-3. Epub 2021 Apr 21.
PD-1, PD-L1, CTLA-4, TIM-3, and LAG-3, crucial immune checkpoint molecules in the tumor microenvironment, identify as key targets for cancer immunotherapy. There is a correlation between immune cells and epithelial-mesenchymal transition (EMT)-related genes expression in varies human cancers. In this study, we aimed to investigate the probable association between expression of immune checkpoints and EMT in esophageal squamous cell carcinoma (ESCC) with clinical treats for providing the new therapeutic targets and prognostic value for the disease. Quantitative real-time PCR was used to investigate the gene expression profile of immune checkpoints (PD-1, PD-L1, CTLA-4, TIM-3, and LAG-3) and EMT (TWIST1 and MMP-13) genes based on the mRNA expression levels in 51 ESCC tissues. The upregulation of CTLA-4, PD-1, PD-L1, TIM-3, LAG-3, MMP-13, and TWIST1 were observed in 31.37%, 29.41%, 21.56%, 39.21%, 25.49%, 60.78%, and 56.86% of ESCC cases at the mRNA level, respectively. Dysregulation of immune checkpoints was related to lymph node involvement, stage of tumor progression, and depth of tumor invasion (P < 0.05). While overexpression of MMP-13 and TWIST1 was associated with lymph node involvement, stage of tumor progression, and grade of tumor differentiation (P < 0.05). The mRNA expression of immune checkpoint genes was significantly correlated to each other's (P = 0.000). Of importance, the data explored the significant association between the concomitant expression of immune checkpoints and EMT-related genes with each other in a variety of clinicopathological traits (P < 0.05). Consequently, immune checkpoints were positively correlated with EMT status in ESCC. The correlation between tumor immune microenvironment with the elevation of multiple immune checkpoints and EMT status may help to identify potential biomarkers for the simultaneous clinical use of multiple immune checkpoints blockade and other immunotherapies approaches for advanced ESCC patients.
PD-1、PD-L1、CTLA-4、TIM-3 和 LAG-3 是肿瘤微环境中至关重要的免疫检查点分子，它们被确定为癌症免疫治疗的关键靶点。在各种人类癌症中，免疫细胞与上皮-间充质转化（EMT）相关基因的表达之间存在相关性。在这项研究中，我们旨在研究免疫检查点和 EMT 在食管鳞状细胞癌（ESCC）中的表达之间可能存在的关联，为该疾病的临床治疗提供新的治疗靶点和预后价值。定量实时 PCR 用于研究免疫检查点（PD-1、PD-L1、CTLA-4、TIM-3 和 LAG-3）和 EMT（TWIST1 和 MMP-13）基因的基因表达谱，基于 51 例 ESCC 组织中的 mRNA 表达水平。在 ESCC 病例中，分别在 31.37%、29.41%、21.56%、39.21%、25.49%、60.78%和 56.86%的病例中观察到 CTLA-4、PD-1、PD-L1、TIM-3、LAG-3、MMP-13 和 TWIST1 的上调。免疫检查点的失调与淋巴结受累、肿瘤进展阶段和肿瘤浸润深度有关（P<0.05）。而 MMP-13 和 TWIST1 的过表达与淋巴结受累、肿瘤进展阶段和肿瘤分化程度有关（P<0.05）。免疫检查点基因的 mRNA 表达彼此之间呈显著相关（P=0.000）。重要的是，数据探索了在各种临床病理特征中，免疫检查点和 EMT 相关基因的伴随表达之间的显著相关性（P<0.05）。因此，在 ESCC 中，免疫检查点与 EMT 状态呈正相关。肿瘤免疫微环境与多个免疫检查点的升高和 EMT 状态之间的相关性可能有助于识别潜在的生物标志物，用于同时使用多种免疫检查点阻断和其他免疫治疗方法治疗晚期 ESCC 患者。
