PDF(Pubmed)
Abstract：
Oxidative stress and the immune microenvironment both contribute to the pathogenesis of esophageal squamous cell carcinoma (ESCC). However, their interrelationships remain poorly understood. We aimed to examine the status of key molecules involved in oxidative stress and the immune microenvironment, as well as their relationships with each other and with clinicopathological features and prognosis in ESCC. The expression of programmed death-ligand 1 (PD-L1), CD8, nuclear factor erythroid-2 related factor-2 (NRF2), and NAD(P)H quinone oxidoreductase 1 (NQO1) was detected using immunohistochemistry in tissue samples from 176 patients with ESCC. We employed both combined positive score (CPS) and tumor proportion score (TPS) to evaluate PD-L1 expression and found a positive correlation between CPS and TPS. Notably, PD-L1 expression, as assessed by either CPS or TPS, was positively correlated with both NRF2 nuclear score and NQO1 score in stage II-IV ESCC. We also observed a positive correlation between the density of CD8+ T cells and PD-L1 expression. Furthermore, high levels of PD-L1 CPS, but not TPS, were associated with advanced TNM stage and lymph node metastases. Moreover, both PD-L1 CPS and the nuclear expression of NRF2 were found to be predictive of shorter overall survival in stage II-IV ESCC. By using the Mandard-tumor regression grading (TRG) system to evaluate the pathological response of tumors to neoadjuvant chemotherapy (NACT), we found that the TRG-5 group had higher NRF2 nuclear score, PD-L1 CPS, and TPS in pre-NACT biopsy samples compared with the TRG-3 + 4 group. The NQO1 scores of post-NACT surgical specimens were significantly higher in the TRG-5 group than in the TRG 3 + 4 group. In conclusion, the expression of PD-L1 is associated with aberrant NRF2 signaling pathway, advanced TNM stage, lymph node metastases, and unfavorable prognosis. The dysregulation of PD-L1 and aberrant activation of the NRF2 signaling pathway are implicated in resistance to NACT. Our findings shed light on the complex interrelationships between oxidative stress and the immune microenvironment in ESCC, which may have implications for personalized therapies and improved patient outcomes.
摘要：
氧化应激和免疫微环境均参与了食管鳞状细胞癌的发病。然而,他们的相互关系仍然知之甚少。我们旨在研究参与氧化应激和免疫微环境的关键分子的状态，以及它们之间以及与ESCC临床病理特征和预后的关系。程序性死亡配体1（PD-L1）的表达，CD8,核因子-2相关因子-2(NRF2),和NAD（P）H醌氧化还原酶1（NQO1）使用免疫组织化学在176例ESCC患者的组织样本中检测。我们采用联合阳性评分（CPS）和肿瘤比例评分（TPS）评估PD-L1表达，发现CPS和TPS之间呈正相关。值得注意的是,PD-L1表达，根据CPS或TPS的评估，在II-IV期ESCC中，NRF2核评分和NQO1评分均呈正相关。我们还观察到CD8+T细胞密度与PD-L1表达之间呈正相关。此外，高水平的PD-L1CPS，但不是TPS，与晚期TNM分期和淋巴结转移有关。此外，PD-L1CPS和NRF2的核表达均可预测II-IV期ESCC的总生存期较短.通过Mandard-肿瘤回归分级(TRG)系统评价肿瘤对新辅助化疗(NACT)的病理反应,我们发现TRG-5组有更高的NRF2核评分，PD-L1CPS,与TRG-3+4组相比，NACT前活检样本中的TPS。NACT术后标本的NQO1评分TRG-5组明显高于TRG3+4组。总之,PD-L1的表达与NRF2信号通路异常有关,高级TNM阶段，淋巴结转移,预后不良。PD-L1的失调和NRF2信号通路的异常激活涉及对NACT的抗性。我们的发现揭示了ESCC中氧化应激和免疫微环境之间复杂的相互关系。这可能对个性化治疗和改善患者预后有影响。
