Tami-12. Cancer-Immune Cell Interactions Drive Transitions to Mesenchymal-Like States in Glioblastoma

Abstract

Communication between cancer cells and immune cells is a key determinant of the glioblastoma ecosystem and its response to therapies, but remains poorly understood. Here we leveraged single-cell RNA-sequencing (scRNA-seq) of human samples and mouse models, deconvolution analysis of bulk specimens from The Cancer Genome Atlas (TCGA) and functional approaches to dissect cellular states and cross-talk in glioblastoma. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived Oncostatin M (OSM) and its cognate receptor OSMR on glioblastoma cells. We show that MES-like glioblastoma states are associated with increased T cells cytotoxicity and potentially with better clinical response to immunotherapies. Overall, our work dissects the cellular interactions within the glioblastoma microenvironment, with potential implications for therapies.

Salmonella-mediated blood‒brain barrier penetration, tumor homing and tumor microenvironment regulation for enhanced chemo/bacterial glioma therapy

“…, engulfing tumor cells, excreting anti-tumor cytokines) and adaptive ( e.g. , antigen presentation) immunity, thus promoting the final therapeutic efficacy 68 , 69 .…”

Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells

“…Such a framework, like the seminal GBM molecular subtype classification scheme (2), will enable integration of the genomic, transcriptomic, and epigenomic landscapes and associated factors that underlie phenotypic plasticity of GSCs and differentiated tumor cells that define intra-and inter-tumoral heterogeneity in GBM (2,4,36,86). Ultimately, a systems approach that connects intrinsic regulatory mechanisms with extrinsic factors, including drug treatment, tumor microenvironment (75), and the immune response (87), governing phenotypic plasticity of GSCs in an individual patient's cancer, will be needed for formulating treatment strategies to prevent recurrence of drug-resistant GBM tumors.…”

Hypoxia coordinates the spatial landscape of myeloid cells within glioblastoma to affect outcome

“…For example, GBM tumours rich in mesenchymal subtype have the highest myeloid cell density, while those abundant in pro-neural subtype show the lowest macrophage proportion (6,50). Myeloid cells can directly shape tumour cell fate, with macrophages being shown to drive differentiation of tumour cells towards a mesenchymal phenotype (51). Further studies are therefore required to address how specific myeloid and neoplastic cell subtypes interact during GBM.…”