Johnson Amanda L, Khela Harmon S, Korleski Jack, Sall Sophie, Li Yunqing, Zhou Weiqiang, Smith-Connor Karen, Laterra John, Lopez-Bertoni Hernando
Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cells. 2025 Apr 14;14(8):592. doi: 10.3390/cells14080592.
Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are poorly defined. In this study, our multifaceted approach combining bioinformatics analyses of clinical and experimental datasets, single-cell sequencing, and the molecular and pharmacologic manipulation of patient-derived cells identified GSCs expressing immunosuppressive effectors mimicking regulatory T cells (Tregs). We showed that this immunosuppressive Treg-like (ITL) GSC state is specific to the mesenchymal GSC subset and is associated with and driven specifically by TGFβ type II receptor (TGFBR2) in contrast to TGFBR1. Transgenic TGFBR2 expression in patient-derived GBM neurospheres promoted a mesenchymal transition and induced a six-gene ITL signature consisting of (PD-L1), (CD73), (CD39), (galectin-1), (PD-L2), and . This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs, and systemic mesenchymal malignancies. TGFBR2 GSCs inhibited CD4+ and CD8+ T cell viability and their capacity to kill GBM cells, effects reversed by pharmacologic and shRNA-based TGFBR2 inhibition. Collectively, our data identify an immunosuppressive GSC state that is TGFBR2-dependent and susceptible to TGFBR2-targeted therapeutics.
由于胶质母细胞瘤（GBM）具有固有的免疫抑制肿瘤微环境，因此激活其抗肿瘤免疫反应面临诸多挑战。分子和表型多样的肿瘤增殖性胶质瘤干细胞（GSCs）导致这种状态的程度和机制尚不清楚。在本研究中，我们采用多方面方法，结合临床和实验数据集的生物信息学分析、单细胞测序以及对患者来源细胞的分子和药理学操作，鉴定出表达模拟调节性T细胞（Tregs）免疫抑制效应分子的GSCs。我们发现这种免疫抑制性Treg样（ITL）GSC状态是间充质GSC亚群特有的，与TGFβ II型受体（TGFBR2）而非TGFBR1相关且由其特异性驱动。患者来源的GBM神经球中转基因TGFBR2表达促进了间充质转变，并诱导了由（PD-L1）、（CD73）、（CD39）、（半乳糖凝集素-1）、（PD-L2）和组成的六基因ITL特征。这种TGFBR2驱动的ITL特征在临床GBM标本、患者来源的GSCs和系统性间充质恶性肿瘤中得到鉴定。TGFBR2 GSCs抑制CD4+和CD8+ T细胞活力及其杀伤GBM细胞的能力，通过基于药理学和shRNA的TGFBR2抑制可逆转这些效应。总体而言，我们的数据确定了一种依赖TGFBR2且易受TGFBR2靶向治疗影响的免疫抑制性GSC状态。
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