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Reprogramming Transcription Factors Oct4 and Sox2 Induce a BRD-Dependent Immunosuppressive Transcriptome in GBM-Propagating Cells.

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机构： [1]Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland. [2]Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital and Collaborative Innovation Center, Sichuan University, Chengdu, China. [3]Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. [4]Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. [5]Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada. [6]Department of Neurosurgery and Oncology, Mayo Clinic, The Johns Hopkins University School of Medicine, Baltimore, Maryland. [7]Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. [8]Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. [9]Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

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A subset of stem-like cells in glioblastoma (GBM; GSC) underlies tumor propagation, therapeutic resistance, and tumor recurrence. Immune evasion is critical for GSCs to carry out these functions. However, the molecular mechanisms employed by GSCs to escape antitumor immunity remain largely unknown. The reprogramming transcription factors Oct4 and Sox2 function as core multipotency factors and play an essential role in the formation and maintenance of GSCs, but the roles of these transcription factors in GSC immune escape have not been well explored. Here we examine how Oct4/Sox2 coexpression contributes to the immunosuppressive phenotype of GSCs. Combined transcription profiling and functional studies of Oct4/Sox2 coexpressing GSCs and differentiated GBM cells demonstrated that Oct4 and Sox2 cooperatively induce an immunosuppressive transcriptome consisting of multiple immunosuppressive checkpoints (i.e., PD-L1, CD70, A2aR, TDO) and dysregulation of cytokines and chemokines that are associated with an immunosuppressive tumor microenvironment. Mechanistically, induction and function of BRD/H3k27Ac-dependent immunosuppressive genes played a role in the immunosuppressive phenotype of GSCs. Pan-BET bromodomain inhibitors (e.g., JQ1) and shBRD4 constructs significantly inhibited the immunosuppressive transcriptome and immunosuppressive biological responses induced by Oct4/Sox2. Our findings identify targetable mechanisms by which tumor-propagating GSCs contribute to the immunosuppressive microenvironment in GBM. SIGNIFICANCE: This report identifies mechanisms by which the reprogramming transcription factors Oct4 and Sox2 function to drive the immunomodulatory transcriptome of GSCs and contribute to the immunosuppressive microenvironment in GBM. ©2021 American Association for Cancer Research.

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出版当年[2021]版：

大类 | 1 区

医学

小类 | 1 区肿瘤学

最新[2023]版：

大类 | 1 区

医学

小类 | 2 区肿瘤学

第一作者：

第一作者机构： [1]Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland. [2]Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital and Collaborative Innovation Center, Sichuan University, Chengdu, China.

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通讯作者：

通讯机构： [1]Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland. [3]Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. [8]Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. [9]Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland. [*1]Hugo W. Moser Research Institute at Kennedy Krieger, The Johns Hopkins School of Medicine, 707 N. Broadway,Baltimore, MD 21205

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