An Immunosuppressive Vascular Niche Drives Macrophage Polarization and Immunotherapy Resistance in Glioblastoma

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2024 Feb 28

PMID 38416830

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

Affiliations

Soon will be listed here.

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.

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