Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
Institute of Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, 400042, Chongqing, China.
Biochem Biophys Res Commun. 2018 Apr 15;498(4):751-757. doi: 10.1016/j.bbrc.2018.03.053. Epub 2018 Mar 17.
Immunotherapy targeting the programmed cell death-1/programmed death ligand 1(PD-L1) pathway has shown promising antitumor activity in brain metastases (BMs) of non-small cell lung cancer (NSCLC) patients with an acceptable safety profile; however, the response rates often differ between primary lesions and intracranial lesions. Studies are necessary to identify detailed characterizations of the response biomarkers. In this study, we aimed to compare the differences of PD-L1 expression and CD8 tumor-infiltrating lymphocyte (TIL) density, two major response biomarkers of PD-1/PD-L1 blockade, between paired primary and brain metastatic lesions in advanced NSCLC. We observed that among primary lesions or BMs, only a small number of patients harbored common PD-L1 expression on both tumor cells and tumor-infiltrating immune cells. Additionally, we found that the numbers of CD8 TILs were significantly fewer in BMs than in primary lung cancers. Low stromal CD8 TIL numbers in BMs were associated with significantly shorter overall survival compared to high stromal CD8 TIL counts. Notably, we demonstrated a discrepancy in PD-L1 expression and CD8 TIL density between primary lung cancers and their corresponding BMs. Such heterogeneities are significantly associated with the time at which BMs occurred. Our study emphasizes the spatial and temporal heterogeneity of biomarkers for anti-PD-1/PD-L1 therapy, which should be concerned in clinical practice.
针对程序性细胞死亡-1/程序性死亡配体 1（PD-L1）通路的免疫疗法在非小细胞肺癌（NSCLC）脑转移（BM）患者中显示出有希望的抗肿瘤活性，且安全性可接受；然而，原发灶和颅内病灶的缓解率往往不同。有必要进行研究以确定 PD-1/PD-L1 阻断的反应生物标志物的详细特征。在这项研究中，我们旨在比较晚期 NSCLC 中配对的原发灶和脑转移灶中 PD-L1 表达和 CD8 肿瘤浸润淋巴细胞（TIL）密度这两个 PD-1/PD-L1 阻断的主要反应生物标志物之间的差异。我们观察到，在原发灶或 BM 中，只有少数患者在肿瘤细胞和肿瘤浸润免疫细胞上都具有常见的 PD-L1 表达。此外，我们发现 BM 中的 CD8 TIL 数量明显少于原发性肺癌。与高基质 CD8 TIL 计数相比，BM 中低基质 CD8 TIL 数量与总生存期明显缩短相关。值得注意的是，我们在原发性肺癌与其相应的 BM 之间证明了 PD-L1 表达和 CD8 TIL 密度存在差异。这种异质性与 BM 发生的时间显著相关。我们的研究强调了抗 PD-1/PD-L1 治疗的生物标志物的空间和时间异质性，这在临床实践中应予以关注。
