The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy.
The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy.
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T 细胞和肿瘤微环境之间的 IFN-gamma/PD-L1 轴：神经胶质瘤抗 PD-1/PD-L1 治疗的提示。
DOI：
10.1186/s12974-018-1330-2
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发表时间：
2018-10-17
影响因子：
9.3
通讯作者：
Chu Y
中科院分区：
文献类型：
--
作者：
Qian J;Wang C;Wang B;Yang J;Wang Y;Luo F;Xu J;Zhao C;Liu R;Chu Y
PD-L1是一种免疫抑制受体配体，通过与其受体PD-1结合，导致T细胞功能障碍和细胞凋亡，PD-1在抑制炎症反应和合谋肿瘤免疫逃逸方面发挥作用。然而，在胶质瘤中，PD-L1在肿瘤微环境中表达的原因尚不清楚。此外，迫切需要辅助生物标志物来筛选可能的反应性脑胶质瘤患者进行抗PD-1/PD-L1治疗。免疫荧光法检测肿瘤浸润性T细胞的分布及PD-L1的表达。用流式细胞仪检测免疫细胞群中PD-L1的表达。从TCGA、LGG/GBM数据集和常青藤胶质母细胞瘤图谱项目中挖掘的数据用于基因与生存相关性的计算机分析。肿瘤浸润性T细胞的分布和PD-L1的表达在小鼠原位胶质瘤模型和人脑胶质瘤显微解剖中是相互关联的。小鼠脑胶质瘤中干扰素-γ水平与PD-L1表达呈正相关。此外，干扰素-γ在原代培养的小胶质细胞、骨髓来源的巨噬细胞和体外培养的GL261胶质瘤细胞上诱导PD-L1表达。选取7个干扰素-γ诱导基因GBP5、ICAM1、CAMK2D、IRF1、SOCS3、CD44和CCL2作为干扰素-γ水平的替代指标进行计算。通过结合列出的干扰素-γ诱导基因的相对表达，在不同解剖结构的人脑胶质瘤和不同恶性肿瘤中，干扰素-γ评分与PD-L1的表达呈正相关。我们的研究确定了肿瘤浸润性T细胞在小鼠胶质瘤模型和人脑胶质瘤标本中的分布和PD-L1的表达。我们发现干扰素-γ是脑胶质瘤微环境中PD-L1表达的重要原因。此外，我们提出了根据列出的干扰素-γ诱导基因的表达聚集的干扰素-γ评分作为抗PD-1/PD-L1治疗的补充预后指标。本文的在线版本(10.1186/s12974-0181330-2)包含向授权用户提供的补充材料。
PD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies. The distribution of tumor-infiltrating T cells and PD-L1 expression was analyzed via immunofluorescence in orthotopic murine glioma model. The expression of PD-L1 in immune cell populations was detected by flow cytometry. Data excavated from TCGA LGG/GBM datasets and the Ivy Glioblastoma Atlas Project was used for in silico analysis of the correlation among genes and survival. The distribution of tumor-infiltrating T cells and PD-L1 expression, which parallels in murine orthotopic glioma model and human glioma microdissections, was interrelated. The IFN-γ level was positively correlated with PD-L1 expression in murine glioma. Further, IFN-γ induces PD-L1 expression on primary cultured microglia, bone marrow-derived macrophages, and GL261 glioma cells in vitro. Seven IFN-γ-induced genes, namely GBP5, ICAM1, CAMK2D, IRF1, SOCS3, CD44, and CCL2, were selected to calculate as substitute indicator for IFN-γ level. By combining the relative expression of the listed IFN-γ-induced genes, IFN-γ score was positively correlated with PD-L1 expression in different anatomic structures of human glioma and in glioma of different malignancies. Our study identified the distribution of tumor-infiltrating T cells and PD-L1 expression in murine glioma model and human glioma samples. And we found that IFN-γ is an important cause of PD-L1 expression in the glioma microenvironment. Further, we proposed IFN-γ score aggregated from the expressions of the listed IFN-γ-induced genes as a complementary prognostic indicator for anti-PD-1/PD-L1 therapy. The online version of this article (10.1186/s12974-018-1330-2) contains supplementary material, which is available to authorized users.
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