Department of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.
Translational Cancer Research Facility, Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
Front Immunol. 2023 May 15;14:1157100. doi: 10.3389/fimmu.2023.1157100. eCollection 2023.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related morbidity and mortality worldwide. Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes with better overall survival, but only 15-40% of the patients respond to ICIs therapy. The search for predictive biomarkers of responses is warranted for better clinical outcomes. We aim here to identify pre-treatment soluble immune molecules as surrogate biomarkers for tissue PD-L1 (TPD-L1) status and as predictors of response to anti-PD-1/PD-L1 therapy in NSCLC patients. Sera from 31 metastatic NSCLC patients, eligible for anti-PD-1/PD-L1 or combined chemoimmunotherapy, were collected prior to treatment. Analysis of soluble biomarkers with TPD-L1 status showed significant up/down regulation of the immune inhibitory checkpoint markers (sSiglec7, sSiglec9, sULBP4 and sPD-L2) in patients with higher TPD-L1 (TPD-L1 >50%) expression. Moreover, correlation analysis showed significant positive linear correlation of soluble PD-L1 (sPD-L1) with higher TPD-L1 expression. Interestingly, only responders in the TPD-L1 >50% group showed significant down regulation of the immune inhibitory markers (sPD-L2, sTIMD4, sNectin2 and CEA). When responders vs. non-responders were compared, significant down regulation of other immune inhibitory biomarkers (sCD80, sTIMD4 and CEA) was recorded only in responding patients. In this, the optimal cut-off values of CD80 <91.7 pg/ml and CEA <1614 pg/ml were found to be significantly associated with better progression free survival (PFS). Indeed, multivariate analysis identified the cutoff-value of CEA <1614 pg/ml as an independent predictor of response in our patients. We identified here novel immune inhibitory/stimulatory soluble mediators as potential surrogate/predictive biomarkers for TPD-L1 status, treatment response and PFS in NSCLC patients treated with anti-PD-1/PD-L1 therapy.
非小细胞肺癌（NSCLC）是全球癌症相关发病率和死亡率的主要原因。免疫检查点抑制剂（ICIs），包括抗 PD-1 和抗 PD-L1 抗体，已经显著改变了治疗结果，总生存率更好，但只有 15-40%的患者对 ICI 治疗有反应。因此，需要寻找预测反应的生物标志物，以获得更好的临床结果。我们旨在确定治疗前可溶性免疫分子作为组织 PD-L1（TPD-L1）状态的替代生物标志物，并作为 NSCLC 患者对抗 PD-1/PD-L1 治疗反应的预测因子。在治疗前收集了 31 名转移性 NSCLC 患者的血清，这些患者有资格接受抗 PD-1/PD-L1 或联合化疗免疫治疗。可溶性生物标志物与 TPD-L1 状态的分析显示，在 TPD-L1 表达较高（TPD-L1>50%）的患者中，免疫抑制检查点标志物（sSiglec7、sSiglec9、sULBP4 和 sPD-L2）的上调/下调具有显著差异。此外，相关性分析显示，可溶性 PD-L1（sPD-L1）与较高的 TPD-L1 表达呈显著正线性相关。有趣的是，只有 TPD-L1>50%组的应答者显示出免疫抑制标志物（sPD-L2、sTIMD4、sNectin2 和 CEA）的显著下调。当比较应答者与无应答者时，仅在应答者中记录到其他免疫抑制生物标志物（sCD80、sTIMD4 和 CEA）的显著下调。在此，CD80<91.7pg/ml 和 CEA<1614pg/ml 的最佳截断值与无进展生存期（PFS）的改善显著相关。事实上，多变量分析确定 CEA<1614pg/ml 的截断值是我们患者反应的独立预测因子。我们在这里确定了新型的免疫抑制/刺激可溶性介质作为潜在的 TPD-L1 状态、治疗反应和 PFS 的替代/预测生物标志物，用于接受抗 PD-1/PD-L1 治疗的 NSCLC 患者。
