Entz-Werle, N. | bioRxiv Science

bioRxiv2024

A coregulatory influence map of glioblastoma heterogeneity and plasticity - From cells in vitro to tumors and back again

We present GBM-cRegMap, an online resource providing a comprehensive coregulatory influence network perspective on glioblastoma (GBM) heterogeneity and plasticity. Using representation learning algorithms, we derived two components of this resource: GBM-CoRegNet, a highly specific coregulatory network of tumor cells, and GBM-CoRegMap, a unified network influence map based on 1612 tumors from 16 studies. As a widely applicable closed-loop system connecting cellular models and tumors, GBM-cRegMap will provide the GBM research community with an easy-to-use web tool (https://gbm.cregmap.com) that maps any existing or newly generated transcriptomic "query" data to a reference coregulatory network and a large-scale manifold of disease heterogeneity. Using GBM-cRegMap, we demonstrated the synergy between the two components by refining the molecular classification of GBM, identifying potential key regulators, and aligning the transcriptional profiles of tumors and in vitro models. Through the amalgamation of a vast dataset, we validated the proneural (PN)-mesenchymal (MES) axis and identified three subclasses of classical (CL) tumors: astrocyte-like (CL-A), epithelial basal-like (CL-B), and cilium-rich (CL-C). We revealed the CL-C subclass, an intermediate state demonstrating the plasticity of GBM cells along the PN-MES axis under chemotherapy. We identified key regulators, such as PAX8, and NKX2.5, involved in TMZ resistance. Notably, NKX2.5, more expressed in higher-grade gliomas, negatively impacts patient survival and regulates genes involved in glucose metabolism. O_FIG O_LINKSMALLFIG WIDTH=152 HEIGHT=200 SRC="FIGDIR/small/609303v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@c7a401org.highwire.dtl.DTLVardef@e0681corg.highwire.dtl.DTLVardef@d31f55org.highwire.dtl.DTLVardef@ae350f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Targeting pediatric High-Grade Gliomas with OAcGD2-CAR Vδ2 T cells

PurposePediatric high-grade gliomas (pHGG) belong to a family of rare childrens cancers which are treated with radiotherapy, based on adult high-grade glioma standard of care. However, new treatments are definitively required since actual ones are unable to extend survival by more than a few months in most patients. In this study, we investigate a Chimeric Antigen Receptor (CAR)-T cell immunotherapy targeting the OAcGD2 ganglioside, using either conventional {beta} or V{delta}2 T cells as effectors. Materials and methodsUsing relevant human primary models of pHGG, we first characterized the innate V{delta}2 T cell immunoreactivity. Then, following the validation of OAcGD2 expression in these tumor cells, we evaluated both {beta} and V{delta}2 OAcGD2-CAR-T cell immunoreactivity using various methods including videomicroscopy, FACS and cytotoxicity assays. ResultsWe showed that pHGG primary cells are not spontaneously recognized and killed by V{delta}2 T cells but significantly expressed the OAcGD2 ganglioside. Accordingly, both {beta} and V{delta}2 T cells engineered to express a CAR against the OAcGD2 efficiently killed pHGG cells in 2D and 3D models. Importantly, only V{delta}2 T cells transduced with the complete OAcGD2-CAR eliminated pHGG cells, in contrast to conventional {beta} CAR-T cells that killed tumor cells even in the absence of CAR expression, highlighting the allogeneic potential of V{delta}2 CAR-T cells. ConclusionOur study demonstrates the preclinical relevance of targeting OAcGD2 in pHGG using CAR-T cells. Furthermore, we also clearly demonstrate the clinical benefits of using V{delta}2 T cells as CAR effectors in allogeneic settings allowing an off-the-shelf immunotherapy.

cancer biology↗