Regulatory T Cell Mimicry by a Subset of Mesenchymal GBM Stem Cells Suppresses CD4 and CD8 Cells
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...
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MDPI AG
2025-04-01
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| author | Amanda L. Johnson Harmon S. Khela Jack Korleski Sophie Sall Yunqing Li Weiqiang Zhou Karen Smith-Connor John Laterra Hernando Lopez-Bertoni |
| author_facet | Amanda L. Johnson Harmon S. Khela Jack Korleski Sophie Sall Yunqing Li Weiqiang Zhou Karen Smith-Connor John Laterra Hernando Lopez-Bertoni |
| author_sort | Amanda L. Johnson |
| collection | DOAJ |
| description | 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 <i>CD274</i> (PD-L1), <i>NT5E</i> (CD73), <i>ENTPD1</i> (CD39), <i>LGALS1</i> (galectin-1), <i>PDCD1LG2</i> (PD-L2), and <i>TGFB1</i>. This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs, and systemic mesenchymal malignancies. TGFBR2<sup>high</sup> 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. |
| format | Article |
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| institution | OA Journals |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-7df2d09373634be6a37b71e51b9e6b362025-08-20T02:24:42ZengMDPI AGCells2073-44092025-04-0114859210.3390/cells14080592Regulatory T Cell Mimicry by a Subset of Mesenchymal GBM Stem Cells Suppresses CD4 and CD8 CellsAmanda L. Johnson0Harmon S. Khela1Jack Korleski2Sophie Sall3Yunqing Li4Weiqiang Zhou5Karen Smith-Connor6John Laterra7Hernando Lopez-Bertoni8Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USAHugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USAHugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USAHugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USAHugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USADepartment of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USAHugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USAHugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USAHugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USAAttempts 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 <i>CD274</i> (PD-L1), <i>NT5E</i> (CD73), <i>ENTPD1</i> (CD39), <i>LGALS1</i> (galectin-1), <i>PDCD1LG2</i> (PD-L2), and <i>TGFB1</i>. This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs, and systemic mesenchymal malignancies. TGFBR2<sup>high</sup> 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.https://www.mdpi.com/2073-4409/14/8/592TGFBR2GBMGSCimmunosuppression |
| spellingShingle | Amanda L. Johnson Harmon S. Khela Jack Korleski Sophie Sall Yunqing Li Weiqiang Zhou Karen Smith-Connor John Laterra Hernando Lopez-Bertoni Regulatory T Cell Mimicry by a Subset of Mesenchymal GBM Stem Cells Suppresses CD4 and CD8 Cells Cells TGFBR2 GBM GSC immunosuppression |
| title | Regulatory T Cell Mimicry by a Subset of Mesenchymal GBM Stem Cells Suppresses CD4 and CD8 Cells |
| title_full | Regulatory T Cell Mimicry by a Subset of Mesenchymal GBM Stem Cells Suppresses CD4 and CD8 Cells |
| title_fullStr | Regulatory T Cell Mimicry by a Subset of Mesenchymal GBM Stem Cells Suppresses CD4 and CD8 Cells |
| title_full_unstemmed | Regulatory T Cell Mimicry by a Subset of Mesenchymal GBM Stem Cells Suppresses CD4 and CD8 Cells |
| title_short | Regulatory T Cell Mimicry by a Subset of Mesenchymal GBM Stem Cells Suppresses CD4 and CD8 Cells |
| title_sort | regulatory t cell mimicry by a subset of mesenchymal gbm stem cells suppresses cd4 and cd8 cells |
| topic | TGFBR2 GBM GSC immunosuppression |
| url | https://www.mdpi.com/2073-4409/14/8/592 |
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