Orphan nuclear receptor TLX promotes immunosuppression via its transcriptional activation of PD-L1 in glioma

作者：Jiayi Zhou, Xiaojuan Pei, Yin-gui Yang, Zhu Wang, Weijie Gao, Ye Ran, Xiantong Zhang, Jiangang Liu, Zhuohao Liu, Xinzhi Yang, Jingli Tao, Chunshan Gu, Wei Hu, Franky Lueng Chan, Xin Li, Jie Mao, Dinglan Wu · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2021 · DOI：10.1136/jitc-2020-001937 · 被引用次数：42 · 研究领域：Glioma Diagnosis and Treatment、Neuroinflammation and Neurodegeneration Mechanisms、Cancer Immunotherapy and Biomarkers

BACKGROUND: High-grade gliomas are rapidly progressing tumors of the central nervous system, and are associated with poor prognosis and highly immunosuppressive microenvironments. Meanwhile, a better understanding of PD-L1, a major prognostic biomarker for checkpoint immune therapy, regulation may provide insights for developing novel immunotherapeutic strategies for treating gliomas. In the present study, we elucidate the functional significance of the orphan nuclear receptor TLX in human glioma, and its functional role in immune suppression through regulation of PD-L1/PD-1 axis. METHODS: TLX and PD-L1 expression patterns, and their association with clinicopathological parameters and immune phenotypes of glioma were analysed using CIBERSORT algorithm and single-sample gene-set enrichment analysis from The Cancer Genome Atlas (n=695) and Chinese Glioma Genome Atlas (n=1018) databases. Protein expression and cellular localization of TLX, PD-L1, and PD-1, as well as the prevalence of cytotoxic tumor-infiltrating lymphocytes (TILs), and tumor-associated macrophages (TAMs), in the glioma immune microenvironment were analyzed via tissue microarray by immunohistochemistry and multiplex immunofluorescence. Glioma allografts and xenografts with TLX manipulation (knockdown/knockout or reverse agonist) were inoculated subcutaneously, or orthotopically into the brains of immunodeficient and immunocompetent mice to assess tumor growth by imaging, and the immune microenvironment by flow c...