Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. 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) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.

Automated summary

The mesenchymal subtype of glioblastoma is believed to be influenced by both cancer cell-intrinsic alterations and external cellular interactions, with macrophages inducing a transition of glioblastoma cells into mesenchymal-like states. This transition is mediated by macrophage-derived oncostatin M (OSM) interacting with its receptors on glioblastoma cells, leading to the activation of STAT3. This study also reveals that mesenchymal-like glioblastoma states are associated with increased expression of a mesenchymal program in macrophages and enhanced cytotoxicity of T cells, suggesting potential therapeutic implications.