Authors: Fan Yang, Md Naushad Akhtar, Duo Zhang, Rakan El-Mayta, Junyoung Shin, Jay F. Dorsey, Lin Zhang, Xiaowei Xu, Wei Guo, Stephen J. Bagley, Serge Y Fuchs, Constantinos Koumenis, Justin D. Lathia, Michael J. Mitchell, Yanqing Gong, Yi Fan
Published: 2024-02-28
Source: Full article
Cancer immunity is subjected to spatiotemporal regulation by leukocyte interaction with neoplastic and stromal cells, contributing to immune evasion and immunotherapy resistance. Here, we identify a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascular niche in glioblastoma (GBM). We reveal a spatially restricted, Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which tumor ECs produce osteopontin to promote immunosuppressive macrophage (Mφ) phenotypes. Genetic or pharmacological ablation of Twist1 reverses Mφ-mediated immunosuppression and enhances T cell infiltration and activation, leading to reduced GBM growth and extended mouse survival, and sensitizing tumor to chimeric antigen receptor T immunotherapy. Thus, these findings uncover a spatially restricted mechanism controlling tumor immunity and suggest that targeting endothelial Twist1 may offer attractive opportunities for optimizing cancer immunotherapy.