探索PDLIM2作为肺腺癌的预后生物标志物和治疗靶点
Exploring PDLIM2 as a prognostic biomarker and therapeutic target in lung adenocarcinoma.
作者
作者单位
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Caris Life Sciences, Phoenix, AZ, USA.
- Georgetown University, Washington, DC, USA.
- Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, USA.
- Montefiore Medical Center, Bronx, New York, NY, USA.
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Zhaoxia.Qu@med.usc.edu.
摘要
中文
尽管PDZ-LIM结构域蛋白（PDLIM2）抑制肺癌，但其临床意义和治疗潜力仍有待充分探索。对15,765例肺腺癌（LUAD）组织进行了下一代测序和程序性死亡配体1（PD-L1）免疫组化。在同基因LUAD小鼠模型中，使用静脉纳米复合质粒DNA单独或联合化学免疫疗法测试了PDLIM2基因治疗。PDLIM2高表达肿瘤在原发/局部活检中较转移样本更常见（73.1% vs 53.0%；p<0.001）。PDLIM2高表达与RB1、TP53、SMARCA4、STK11和KEAP1的较低突变率相关，但EGFR突变增加（所有p<0.01）。PDLIM2高表达肿瘤还显示免疫细胞浸润增加、T细胞炎症评分升高和PD-L1阳性率增加（所有p<0.008）。高PDLIM2与改善的生存期相关（24.1 vs 18.1个月；p<0.001，HR=0.84），多变量分析中仍保持预后意义（HR=0.88，95% CI 0.83-0.93），以及与更长的pembrolizumab治疗时间相关，尤其是联合铂类治疗时（p=0.012，HR=0.867）。在两个LUAD小鼠模型中，与单独化学免疫疗法相比，nanoPDLIM2改善了中位总生存期（10-12.5 vs 8-9天；N=8；p=0.0001，0.0003）。PDLIM2是与免疫反应性肿瘤相关的LUAD有前景的预后生物标志物。临床前，基于PDLIM2的疗法增强了化学免疫疗法的疗效，但其预测作用需进一步评估。
English
While PDZ-LIM domain-containing protein (PDLIM2) suppresses lung cancer, its clinical significance and therapeutic potential remain to be fully explored. Next-generation sequencing and immunohistochemistry of programmed death ligand 1 (PD-L1) were performed on lung adenocarcinoma (LUAD) tissues from 15,765 patients. PDLIM2 gene therapy was tested in syngeneic LUAD mouse models using intravenous nano-complexed plasmid DNA, alone or with chemoimmunotherapy. PDLIM2-high tumors were more common in primary/local biopsies versus metastatic samples (73.1% vs 53.0%; p < 0.001). High PDLIM2 expression was linked to lower mutation rates in RB1, TP53, SMARCA4, STK11, and KEAP1, but increased EGFR mutations (all p < 0.01). PDLIM2-high tumors also showed increased immune cell infiltration, T cell-inflamed scores, and PD-L1 positivity (all p < 0.008). High PDLIM2 was associated with improved survival (24.1 vs 18.1 months; p < 0.001, HR = 0.84) and remained prognostic in multivariate analysis (HR = 0.88, 95% CI 0.83-0.93), as well as with longer pembrolizumab time, especially with platinum-based therapy (p = 0.012, HR = 0.867). In two LUAD mouse models, nanoPDLIM2 improved median overall survival versus chemoimmunotherapy alone (10-12.5 vs 8-9 days; N = 8; p = 0.0001, 0.0003). PDLIM2 is a promising prognostic biomarker in LUAD linked to immune-receptive tumors. Preclinically, PDLIM2-based therapy enhances chemoimmunotherapy efficacy, though its predictive role warrants further evaluation.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 7.8
- 新锐分区
- 1区