Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
PLoS One. 2022 Dec 1;17(12):e0277908. doi: 10.1371/journal.pone.0277908. eCollection 2022.
The expression/activation of IL-6, p-Stat3, PD-1 and PD-L1 in gastric cancer (GC) tissues were examined to evaluate their abilities in predicting the survival prognosis in postoperative patients with GC.
The clinicopathological data and paraffin-embedded tissues of 205 patients who underwent gastric cancer resection were collected at the First Affiliated Hospital of Shihezi University School of Medicine, and the patients were followed-up annually after surgery. Immunohistochemistry (IHC) was used to detect the expression of IL-6, p-Stat3, PD-1 and PD-L1 proteins using tissue microarrays derived from these patients. Statistical analyses were performed using non-parametric tests, Spearman's correlation, ROC curves, Kaplan-Meier survival analysis, Cox single-factor and multifactor regression models. In comparison, the analyses were also performed for GC patients from public databases (407 patients from TCGA and 433 patients from GEO, respectively).
(1) The expression levels of IL-6, p-Stat3, PD-1 and PD-L1 in GC tissues were significantly higher than adjacent normal tissues (ANT) (81.01% vs. 52.78%, P<0.001; 100% vs. 93.41%, P<0.001; 58.58% vs. 40.12%, P<0.001; 38.20% vs. 26.90%, P = 0.025, respectively). The mean optical density (MOD) values of IL-6, p-Stat3, PD-1 and PD-L1 were significantly higher in GC tissues. (2) The higher the levels of IL-6 (P<0.001), p-Stat3 (P<0.001), and PD-L1 (P = 0.003) were, the worse the survival prognoses were observed, respectively, among GC patients. The expression of PD-1 was not correlated with the prognosis of GC patients (P>0.05). The lower the degree of cell differentiation (P<0.001) was, the worse the survival prognoses were observed among GC patients. (3) Independent risk factors for postoperative prognosis in GC patients included age (≥60 years old), poor cell differentiation, invasion depth (T3/T4), lymph node metastasis (N1-3), distant metastasis (M1), and high levels of IL-6 (2+/3+). (4) A multi-factor combination (cell differentiation+IL-6+p-Stat3+PD-1+PD-L1) appeared to be the best survival predictor for GC patients as indicated by AUC (AUC 0.782, 95% CI = 0.709, 0.856, P<0.001). This combination may be the optimal predictor for postoperative survival of GC patients. (5) The levels of IL-6, p-Stat3, PD-1 and PD-L1 correlated with the infiltration levels of various tumor-infiltrating immune cells. (6) The analyses of ROC curves, calibration, DCA and Kaplan-Meier (KM) survival curves in TCGA dataset confirmed that the nomogram model could accurately predict the prognosis in GC patients.
(1) The expressed levels of IL-6, p-Stat3, PD-1 and PD-L1 are higher in GC tissues than in adjacent normal tissues. (2) The high levels of IL-6, p-Stat3 and PD-L1 are correlated with poor survival in GC patients. (3) The high levels of IL-6, p-Stat3, PD-1 and PD-L1 have influences in GC tumor microenvironment. (4) The multi-predictor combination of "IL-6+p-Stat3+PD-1+cell differentiation" serves as an optimal survival predictor for postoperative GC patients and better than the TNM staging system. As these molecules can be examined in preoperative biopsies, these observations may provide a useful guide for clinicians to strategize individualized surgical plans for GC patients before surgery.
检测胃癌（GC）组织中 IL-6、p-Stat3、PD-1 和 PD-L1 的表达/激活情况，评估其预测 GC 术后患者生存预后的能力。
收集石河子大学医学院第一附属医院 205 例胃癌切除术后患者的临床病理资料和石蜡包埋组织，术后每年进行随访。采用组织微阵列免疫组织化学（IHC）检测这些患者组织中 IL-6、p-Stat3、PD-1 和 PD-L1 蛋白的表达。使用非参数检验、Spearman 相关性分析、ROC 曲线、Kaplan-Meier 生存分析、Cox 单因素和多因素回归模型进行统计分析。此外，还对来自公共数据库（TCGA 数据库中 407 例患者和 GEO 数据库中 433 例患者）的 GC 患者进行了分析。
（1）GC 组织中 IL-6、p-Stat3、PD-1 和 PD-L1 的表达水平明显高于相邻正常组织（ANT）（81.01%比 52.78%，P<0.001；100%比 93.41%，P<0.001；58.58%比 40.12%，P<0.001；38.20%比 26.90%，P=0.025）。GC 组织中 IL-6、p-Stat3、PD-1 和 PD-L1 的平均光密度（MOD）值均明显升高。（2）IL-6（P<0.001）、p-Stat3（P<0.001）和 PD-L1（P=0.003）水平越高，GC 患者的生存预后越差。PD-1 的表达与 GC 患者的预后无关（P>0.05）。GC 患者的细胞分化程度越低，生存预后越差。（3）GC 患者术后预后的独立危险因素包括年龄（≥60 岁）、细胞分化差、浸润深度（T3/T4）、淋巴结转移（N1-3）、远处转移（M1）和高 IL-6 水平（2+/3+）。（4）多因素组合（细胞分化+IL-6+p-Stat3+PD-1+PD-L1）似乎是 GC 患者最佳的生存预测因子，AUC（0.782，95%CI=0.709，0.856，P<0.001）。这种组合可能是 GC 患者术后生存的最佳预测因子。（5）IL-6、p-Stat3、PD-1 和 PD-L1 的水平与各种肿瘤浸润免疫细胞的浸润水平相关。（6）在 TCGA 数据集的 ROC 曲线、校准、DCA 和 Kaplan-Meier（KM）生存曲线分析中证实，列线图模型能够准确预测 GC 患者的预后。
（1）GC 组织中 IL-6、p-Stat3、PD-1 和 PD-L1 的表达水平高于相邻正常组织。（2）IL-6、p-Stat3 和 PD-L1 的高水平与 GC 患者的不良生存相关。（3）IL-6、p-Stat3、PD-1 和 PD-L1 对 GC 肿瘤微环境有影响。（4）“IL-6+p-Stat3+PD-1+细胞分化”的多预测因子组合是 GC 术后患者的最佳生存预测因子，优于 TNM 分期系统。由于这些分子可以在术前活检中检查，这些观察结果可能为临床医生在术前为 GC 患者制定个体化手术计划提供有用的指导。
