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CAR T-cell design dependent remodeling of the brain tumor immune microenvironment identify macrophages as key players that inhibit or promote anti-tumor activity.

Dalia HaydarJorge Ibañez-VegaJeremy CrawfordChing-Heng ChouCliff GuyMichaela MeehlZhongzhen YiDeanna M LangfittPeter VogelChristopher DeRenzoStephen GottschalkMartine F RousselPaul Glyndwr ThomasGiedre Krenciute
Published in: Research square (2023)
Understanding interactions between adoptively transferred immune cells and the tumor immune microenvironment (TIME) is critical for developing successful T-cell based immunotherapies. Here we investigated the impact of the TIME and chimeric antigen receptor (CAR) design on anti-glioma activity of B7-H3-specific CAR T-cells. We show that five out of six B7-H3 CARs with varying transmembrane, co-stimulatory, and activation domains, exhibit robust functionality in vitro . However, in an immunocompetent glioma model, these CAR T-cells demonstrated significantly varied levels of anti-tumor activity. We used single-cell RNA sequencing to examine the brain TIME after CAR T-cell therapy. We show that the TIME composition was influenced by CAR T-cell treatment. We also found that successful anti-tumor responses were supported by the presence and activity of macrophages and endogenous T-cells. Together, our study demonstrates that efficacy of CAR T-cell therapy in high-grade glioma is dependent on CAR structural design and its capacity to modulate the TIME.
Keyphrases
  • cell therapy
  • single cell
  • stem cells
  • high grade
  • mesenchymal stem cells
  • rna seq
  • bone marrow
  • mass spectrometry
  • high resolution
  • resting state
  • replacement therapy
  • subarachnoid hemorrhage