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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. 

Abstract The role of plasticity and epigenetics in shaping cancer evolution and response to therapy has taken center stage with recent technological advances including single cell sequencing. This roadmap article is focused on state-of-the-art mathematical and experimental approaches to interrogate plasticity in cancer, and addresses the following themes and questions: is there a formal overarching framework that encompasses both non-genetic plasticity and mutation-driven somatic evolution? How do we measure and model the role of the microenvironment in influencing/controlling non-genetic plasticity? How can we experimentally study non-genetic plasticity? Which mathematical techniques are required or best suited? What are the clinical and practical applications and implications of these concepts?