Boffa Daniel J, Graf Ryon P, Salazar Michelle C, Hoag Jessica, Lu David, Krupa Rachel, Louw Jessica, Dugan Lyndsey, Wang Yipeng, Landers Mark, Suraneni Mahipal, Greene Stephanie B, Magaña Marisa, Makani Samir, Bazhenova Lyudmila, Dittamore Ryan V, Nieva Jorge
Section of Thoracic Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
Epic Sciences, San Diego, California.
Cancer Epidemiol Biomarkers Prev. 2017 Jul;26(7):1139-1145. doi: 10.1158/1055-9965.EPI-17-0120. Epub 2017 Apr 26.
Lung cancer treatment has become increasingly dependent upon invasive biopsies to profile tumors for personalized therapy. Recently, tumor expression of programmed death-ligand 1 (PD-L1) has gained interest as a potential predictor of response to immunotherapy. Circulating biomarkers present an opportunity for tumor profiling without the risks of invasive procedures. We characterized PD-L1 expression within populations of nucleated cells in the peripheral blood of lung cancer patients in hopes of expanding the role of liquid biopsy in this setting. Peripheral blood samples from a multi-institutional prospective study of patients with clinical diagnosis of lung cancer were subjected to cytomorphometric and immunohistochemical evaluation using single-cell, automated slide-based, digital pathology. PD-L1 expression was determined by immunofluorescence. PD-L1 expression was detected within peripheral circulating cells associated with malignancy (CCAM) in 26 of 112 (23%) non-small cell lung cancer patients. Two distinct populations of nucleated, nonhematolymphoid, PD-L1-expressing cells were identified; cytokeratin positive (CK+, PD-L1+, CD45) and cytokeratin negative (CK-, PD-L1+, CD45) cells, both with cytomorphometric features (size, nuclear-to-cytoplasm ratio) consistent with tumor cells. Patients with >1.1 PD-L1(+) cell/mL ( = 14/112) experienced worse overall survival than patients with ≤1.1 PD-L1(+) cell/mL (2-year OS: 31.2% vs. 78.8%, = 0.00159). In a Cox model adjusting for stage, high PD-L1(+) cell burden remained a significant predictor of mortality (HR = 3.85; 95% confidence interval, 1.64-9.09; = 0.002). PD-L1 expression is detectable in two distinct cell populations in the peripheral blood of lung cancer patients and is associated with worse survival. These findings could represent a step forward in the development of minimally invasive liquid biopsies for the profiling of tumors. .
肺癌治疗越来越依赖侵入性活检来分析肿瘤以进行个性化治疗。最近，程序性死亡配体1（PD-L1）的肿瘤表达作为免疫治疗反应的潜在预测指标受到关注。循环生物标志物为肿瘤分析提供了机会，且无侵入性操作的风险。我们对肺癌患者外周血中有核细胞群体内的PD-L1表达进行了特征分析，以期扩大液体活检在此种情况下的作用。来自一项对临床诊断为肺癌患者的多机构前瞻性研究的外周血样本，采用单细胞、基于玻片自动成像的数字病理学进行细胞形态计量学和免疫组织化学评估。通过免疫荧光测定PD-L1表达。在112例非小细胞肺癌患者中的26例（23%）的外周循环恶性相关细胞（CCAM）中检测到PD-L1表达。鉴定出两种不同的有核、非血液淋巴样、表达PD-L1的细胞群体；细胞角蛋白阳性（CK+，PD-L1+，CD45-）和细胞角蛋白阴性（CK-，PD-L1+，CD45-）细胞，两者均具有与肿瘤细胞一致的细胞形态计量学特征（大小、核质比）。每毫升血液中PD-L1(+)细胞>1.1个的患者（n = 14/112）的总生存期比每毫升血液中PD-L1(+)细胞≤1.1个的患者更差（2年总生存率：31.2%对78.8%，P = 0.00159）。在调整分期的Cox模型中，高PD-L1(+)细胞负荷仍然是死亡率的显著预测指标（风险比 = 3.85；95%置信区间，1.64 - 9.09；P = 0.002）。在肺癌患者外周血的两种不同细胞群体中可检测到PD-L1表达，且与较差的生存率相关。这些发现可能代表了用于肿瘤分析的微创液体活检技术发展的一个进步。
