An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma.

in Science advances by 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

TLDR

  • The study found that a certain type of cells in the brain called glioblastoma (GBM) have a special way of communicating with other cells that helps them grow and survive. The study identified a specific type of these cells that form a special area in the brain that helps them grow and survive. The study also found out how these cells communicate with other cells to help them grow and survive. The study found that if you remove a certain protein from these cells, they stop communicating with other cells and the brain tumor shrinks. The study also found that this treatment makes the brain tumor more sensitive to a type of treatment called immunotherapy.

Abstract

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.

Overview

  • The study investigates the role of leukocyte interaction with neoplastic and stromal cells in cancer immunity and how it contributes to immune evasion and immunotherapy resistance. The study identifies a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascular niche in glioblastoma (GBM). The study aims to understand the mechanisms underlying the formation of this vascular niche and its impact on GBM growth and immunotherapy response. The primary objective of the study is to identify potential targets for optimizing cancer immunotherapy.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, specifically genetic or pharmacological ablation of Twist1, which reverses Mφ-mediated immunosuppression and enhances T cell infiltration and activation. The study identifies a spatially restricted, Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which tumor ECs produce osteopontin to promote immunosuppressive macrophage (Mφ) phenotypes. The key findings of the study suggest that targeting endothelial Twist1 may offer attractive opportunities for optimizing cancer immunotherapy.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they uncover a spatially restricted mechanism controlling tumor immunity. The study identifies potential targets for optimizing cancer immunotherapy, specifically targeting endothelial Twist1. The study suggests that future research directions could explore the use of Twist1 inhibitors in combination with other immunotherapies to enhance their efficacy. The study also highlights the importance of understanding the spatial regulation of tumor immunity and the role of leukocyte interaction with neoplastic and stromal cells in immune evasion and immunotherapy resistance.
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