PO.CL05.06 · 临床研究
肿瘤细胞NY-ESO-1表达预测NSCLC中PD-1/PD-L1阻断的不良应答
Tumor-cell NY-ESO-1 expression predicts poor response to PD-1/PD-L1 blockade in NSCLC
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摘要 Abstract
中文摘要
背景：NY-ESO-1是一种免疫原性癌-睾丸抗原，也是基于TCR策略的治疗靶点。其作为非小细胞肺癌（NSCLC）接受PD-1/PD-L1抑制剂治疗的基线生物标志物的意义尚未得到充分确立。由于NY-ESO-1仅在由肿瘤上皮细胞表达时才具有生物学相关性，我们将分析专门聚焦于CK7⁺肿瘤细胞内的NY-ESO-1表达，并评估其与接受免疫检查点阻断患者临床结局的关联。
方法：使用一种经验证的多重免疫荧光板（包括CD8、CD68、CD103、CK7、HLA-ABC、cMAF、NY-ESO-1和pSMAD3）对195例接受PD-1/PD-L1抑制剂治疗的晚期NSCLC患者的基线FFPE肿瘤样本进行分析。在信号归一化后，使用Vectra Polaris成像、QuPath分割和基于FlowJo的表型分析进行数字图像分析。肿瘤特异性NY-ESO-1表达定义为CK7⁺/NYESO1⁺共定位。使用Wilcoxon检验、卡方检验和基于切点的生存建模评估其与RECIST应答、持久临床获益（DCB）、无进展生存期（PFS）和总生存期（OS）的关联。还计算了CK7→CD8和CK7→CD68细胞间距离。
结果：较高的CK7⁺/NY-ESO-1⁺肿瘤细胞水平与PD-1/PD-L1阻断无应答显著相关（p=0.011），NY-ESO-1表达强度增加也与无应答相关（p=0.044）。肿瘤局限性NY-ESO-1强烈预测较短的生存期。高CK7⁺/NY-ESO-1⁺肿瘤表达患者的中位PFS为1.8个月，而低表达组为8.1个月（p=7.2×10⁻⁵）。中位OS同样降低，高表达组为11.0个月，而低表达组为33.5个月（p=3.9×10⁻³）。高肿瘤NY-ESO-1还与持久临床获益的大幅降低相关（χ² p=0.013）。独立于NY-ESO-1，更大的CK7→CD8和CK7→CD68距离预测较差的PFS和OS，尽管未评估NY-ESO-1水平与空间距离之间的直接关联。
结论：肿瘤细胞NY-ESO-1表达是NSCLC接受PD-1/PD-L1抑制剂治疗的一个稳健不良生物标志物。高CK7⁺/NY-ESO-1⁺肿瘤负荷可识别出PFS和OS显著降低、应答率较低以及获得持久临床获益可能性较差的患者。这些发现支持肿瘤局限性NY-ESO-1作为免疫治疗结局的临床有意义的负性基线预测因子的作用，并可能有助于优化针对NY-ESO-1靶向治疗的患者选择。
查看英文原文 English abstract
Background: NY-ESO-1 is an immunogenic cancer-testis antigen and a therapeutic target for TCR-based strategies. Its significance as a baseline biomarker in non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors is not well established. Because NY-ESO-1 has biological relevance only when expressed by tumor epithelial cells, we focused our analysis specifically on NY-ESO-1 expression within CK7⁺ tumor cells and evaluated its association with clinical outcomes in patients receiving immune checkpoint blockade.
Methods: Baseline FFPE tumor samples from 195 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors were profiled using a validated multiplex immunofluorescence panel including CD8, CD68, CD103, CK7, HLA-ABC, cMAF, NY-ESO-1, and pSMAD3. Digital image analysis was performed using Vectra Polaris imaging, QuPath segmentation, and FlowJo-based phenotyping after signal normalization. Tumor-specific NY-ESO-1 expression was defined by CK7⁺/NYESO1⁺ co-localization. Associations with RECIST response, durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS) were assessed using Wilcoxon tests, chi-square tests, and cutpoint-based survival modeling. CK7→CD8 and CK7→CD68 intercellular distances were also computed.
Results: Higher CK7⁺/NY-ESO-1⁺ tumor cell levels were significantly associated with non-response to PD-1/PD-L1 blockade (p=0.011), and increased NY-ESO-1 expression intensity also associated with non-response (p=0.044). Tumor-restricted NY-ESO-1 was strongly predictive of shorter survival. Patients with high CK7⁺/NY-ESO-1⁺ tumor expression had a median PFS of 1.8 months, compared with 8.1 months in the low-expression group (p=7.2×10⁻⁵). Median OS was similarly reduced, with 11.0 months in the high-expression group versus 33.5 months in the low-expression group (p=3.9×10⁻³). High tumor NY-ESO-1 also correlated with substantially reduced durable clinical benefit (χ² p=0.013). Independently of NY-ESO-1, greater CK7→CD8 and CK7→CD68 distances predicted inferior PFS and OS, although no direct association between NY-ESO-1 levels and spatial distances was assessed.
Conclusions: Tumor-cell NY-ESO-1 expression is a robust adverse biomarker in NSCLC treated with PD-1/PD-L1 inhibitors. High CK7⁺/NY-ESO-1⁺ tumor burden identifies patients with dramatically reduced PFS and OS, lower response rates, and poor likelihood of achieving durable clinical benefit. These findings support the role of tumor-restricted NY-ESO-1 as a clinically meaningful negative baseline predictor of immunotherapy outcome and may help refine patient selection for NY-ESO-1-targeted therapies.
利益披露 Disclosure
A. Lerue, None..
A. Italiano, None.