Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado.
Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, New York.
J Thorac Oncol. 2019 Jan;14(1):25-36. doi: 10.1016/j.jtho.2018.09.006. Epub 2018 Sep 22.
Anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy has demonstrated success in the treatment of advanced NSCLC. Recently, PD-1/PD-L1 blockade also has demonstrated interesting results in small trials of neoadjuvant treatment in stage IB to IIIA NSCLC. In addition, several clinical trials using anti-PD-1/PD-L1 immunotherapy as an adjuvant or neoadjuvant treatment in patients with resectable stage NSCLC are ongoing. However, few analyses of anti-PD-1/PD-L1 immunotherapy-related biomarkers in early-stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC, providing data for identifying the potential role for patients with anti-PD-1/PD-L1 treatment in early-stage SqCLC.
A total of 255 specimens from patients with early-stage SqCLC were identified within participating centers of the Strategic Partnering to Evaluate Cancer Signatures program. PD-L1 protein expression by immunohistochemistry was evaluated by using the Dako PD-L1 22C3 pharmDx kit on the Dako Link 48 auto-stainer (Dako, Carpinteria, CA). Tumor mutation burden (TMB) was calculated on the basis of data from targeted genome sequencing. The T-effector and interferon gamma (IFN-γ) gene signature was determined from Affymetrix gene chip data (Affymetrix, Santa Clara, CA) from frozen specimens.
The prevalence of PD-L1 expression was 9.8% at a tumor proportion score cutoff of at least 50%. PD-L1 mRNA and programmed cell death 1 ligand 2 mRNA positively correlated with PD-L1 protein expression on tumor cells (TCs) and tumor-infiltrating immune cells. PD-L1 protein expression on tumor-infiltrating immune cells was correlated with the T-effector and IFN-γ gene signature (p < 0.001), but not with TMB. For TCs, all of these biomarkers were independent of each other and neither PD-L1 protein expression, TMB, or T-effector and IFN-γ gene signatures were independently prognostic for patient outcomes.
Evaluation of PD-L1 expression, TMB, and T-effector and IFN-γ gene signatures in the cohort with early-stage SqCLC found them to be independent of each other, and none was associated with overall survival. Our results also support the hypothesis that PD-L1 expression is regulated by an intrinsic mechanism on TCs and an adaptive mechanism on immune cells.
抗程序性细胞死亡 1（PD-1）/程序性死亡配体 1（PD-L1）免疫疗法已在晚期非小细胞肺癌（NSCLC）的治疗中取得成功。最近，PD-1/PD-L1 阻断剂在 IB 期至 IIIA 期 NSCLC 的新辅助治疗小试验中也显示出了有趣的结果。此外，几项使用抗 PD-1/PD-L1 免疫疗法作为可切除的 I 期 NSCLC 辅助或新辅助治疗的临床试验正在进行中。然而，关于早期鳞状细胞肺癌（SqCLC）中抗 PD-1/PD-L1 免疫治疗相关生物标志物的分析很少。在本研究中，我们评估了早期 SqCLC 中 PD-L1 蛋白表达、肿瘤突变负担和免疫基因特征的表达，为识别早期 SqCLC 患者接受抗 PD-1/PD-L1 治疗的潜在作用提供了数据。
在参与癌症特征战略合作计划的参与中心中，共鉴定了 255 例早期 SqCLC 患者的标本。使用 Dako PD-L1 22C3 pharmDx 试剂盒（Dako，Carpinteria，CA），在 Dako Link 48 自动染色机（Dako，Carpinteria，CA）上通过免疫组织化学评估 PD-L1 蛋白表达。基于靶向基因组测序数据计算肿瘤突变负担（TMB）。从冷冻标本的 Affymetrix 基因芯片数据（Affymetrix，Santa Clara，CA）中确定 T 效应细胞和干扰素 γ（IFN-γ）基因特征。
在肿瘤比例评分截断值至少为 50%时，PD-L1 表达的患病率为 9.8%。PD-L1 mRNA 和程序性死亡配体 2 mRNA 与肿瘤细胞（TCs）和肿瘤浸润免疫细胞上的 PD-L1 蛋白表达呈正相关。肿瘤浸润免疫细胞上的 PD-L1 蛋白表达与 T 效应细胞和 IFN-γ基因特征相关（p<0.001），但与 TMB 无关。对于 TCs，所有这些生物标志物彼此独立，PD-L1 蛋白表达、TMB 或 T 效应细胞和 IFN-γ 基因特征均不能独立预测患者预后。
对早期 SqCLC 队列中 PD-L1 表达、TMB 和 T 效应细胞和 IFN-γ 基因特征的评估发现，它们彼此独立，均与总生存期无关。我们的结果还支持 PD-L1 表达由 TCs 的内在机制和免疫细胞的适应性机制调节的假设。
