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bioRxiv · 10.1101/2025.01.07.631757

TGFBR2-High mesenchymal glioma stem cells phenocopy regulatory T cells to suppress CD4+ and CD8+ T cell function

Johnson, A. L.·Khela, H. S.·Korleski, J.·Sall, S.·Li, Y.·Zhou, W.·Smith-Connor, K.·Lopez-Bertoni, H.·Laterra, J.
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Abstract

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 molecular and pharmacologic manipulation of patient-derived cells identified GSCs expressing immunosuppressive effectors mimicking regulatory T cells (Tregs). We show that this Immunosuppressive Treg-Like (ITL) GSC state is specific to the mesenchymal GSC subset and is associated with and driven specifically by TGF-{beta} type II receptor (TGFBR2) in contrast to TGFBR1. Transgenic TGFBR2 expression in patient-derived GBM neurospheres promoted a mesenchymal transition and induced a 6-gene ITL signature consisting of CD274 (PD-L1), NT5E (CD73), ENTPD1 (CD39), LGALS1 (galectin-1), PDCD1LG2 (PD-L2), and TGFB1. This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs and systemic mesenchymal malignancies. TGFBR2High 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.

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Johnson, A. L., Khela, H. S., Korleski, J., Sall, S., Li, Y., Zhou, W., Smith-Connor, K., Lopez-Bertoni, H., Laterra, J.. 2025-01-08. TGFBR2-High mesenchymal glioma stem cells phenocopy regulatory T cells to suppress CD4+ and CD8+ T cell function. https://doi.org/10.1101/2025.01.07.631757

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