Department of Spine Surgery, The Second Xiangya Hospital, Central South University, 139 Renminzhong Road, Changsha, Hunan, 410011, China.
Institute of Precision Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
Cancer Immunol Immunother. 2018 Feb;67(2):209-224. doi: 10.1007/s00262-017-2080-1. Epub 2017 Oct 20.
Currently, little is known about the interactions between microRNAs (miRNAs) and the PD-1/PD-L1 signaling pathway in chordoma, and data discussing the role of the immune milieu in chordoma prognosis are limited. We aimed to analyze the relationship between PD-L1, miR-574-3p, microenvironmental tumor-infiltrating lymphocytes (TILs) and clinicopathological features of spinal chordoma patients. PD-L1 expression and TILs (including Foxp3, CD8, PD-1 and PD-L1) were assessed by immunohistochemistry in tumor specimens of 54 spinal chordoma patients. MiRNAs microarray and bioinformatical analysis were used to identify miRNAs potentially regulating PD-L1 expression, which were further validated by quantitative RT-PCR. miR-574-3p was identified to potentially regulate PD-L1 expression in chordoma, which inversely correlated with PD-L1. Positive PD-L1 expression on tumor cells was associated with advanced stages (P = 0.041) and TILs infiltration (P = 0.005), whereas decreased miR-574-3p level correlated with higher muscle invasion (P = 0.012), more severe tumor necrosis (P = 0.022) and poor patient survival. Importantly, a patient subgroup with PD-L1/miR-574-3p chordoma phenotype was significantly associated with worse local recurrence-free survival (LRFS) (P = 0.026). PD-1 TILs density was associated with surrounding muscle invasion (P = 0.014), and independently portended poor LRFS (P = 0.040), while PD-L1 TILs showed tendencies of less aggressive clinical outcomes. Multivariate analysis of OS only found CD8/Foxp3 ratio to be independent prognostic factor (P = 0.022). These findings may be useful to stratify patients into prognostic groups and provide a rationale for the use of checkpoint blockade therapy, possibly by administering miR-574-3p mimics, in spinal chordoma.
目前，人们对 miRNA（miRNAs）与 PD-1/PD-L1 信号通路在脊索瘤中的相互作用知之甚少，并且讨论免疫微环境在脊索瘤预后中的作用的数据也很有限。我们旨在分析 PD-L1、miR-574-3p、肿瘤浸润淋巴细胞（TILs）与脊索瘤患者临床病理特征之间的关系。通过免疫组化检测 54 例脊索瘤患者肿瘤标本中的 PD-L1 表达和 TILs（包括 Foxp3、CD8、PD-1 和 PD-L1）。使用 miRNA 微阵列和生物信息学分析来鉴定潜在调节 PD-L1 表达的 miRNAs，并用定量 RT-PCR 进一步验证。miR-574-3p 被鉴定为潜在调节脊索瘤中 PD-L1 的表达，与 PD-L1 呈负相关。肿瘤细胞上的 PD-L1 阳性表达与晚期（P=0.041）和 TILs 浸润（P=0.005）相关，而 miR-574-3p 水平降低与更高的肌肉浸润（P=0.012）、更严重的肿瘤坏死（P=0.022）和较差的患者生存相关。重要的是，具有 PD-L1/miR-574-3p 脊索瘤表型的患者亚组与局部无复发生存率（LRFS）更差显著相关（P=0.026）。PD-1 TILs 密度与周围肌肉浸润相关（P=0.014），并独立预示着较差的 LRFS（P=0.040），而 PD-L1 TILs 则显示出侵袭性临床结局的趋势。OS 的多变量分析仅发现 CD8/Foxp3 比值是独立的预后因素（P=0.022）。这些发现可能有助于将患者分层为预后组，并为使用检查点阻断疗法提供依据，可能通过给予 miR-574-3p 模拟物，用于治疗脊索瘤。
