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Open Access Green as soon as Postprint is submitted to ZB.
Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma.
Cell 187, 149-165.e23 (2024)
Deciphering the cell-state transitions underlying immune adaptation across time is fundamental for advancing biology. Empirical in vivo genomic technologies that capture cellular dynamics are currently lacking. We present Zman-seq, a single-cell technology recording transcriptomic dynamics across time by introducing time stamps into circulating immune cells, tracking them in tissues for days. Applying Zman-seq resolved cell-state and molecular trajectories of the dysfunctional immune microenvironment in glioblastoma. Within 24 hours of tumor infiltration, cytotoxic natural killer cells transitioned to a dysfunctional program regulated by TGFB1 signaling. Infiltrating monocytes differentiated into immunosuppressive macrophages, characterized by the upregulation of suppressive myeloid checkpoints Trem2, Il18bp, and Arg1, over 36 to 48 hours. Treatment with an antagonistic anti-TREM2 antibody reshaped the tumor microenvironment by redirecting the monocyte trajectory toward pro-inflammatory macrophages. Zman-seq is a broadly applicable technology, enabling empirical measurements of differentiation trajectories, which can enhance the development of more efficacious immunotherapies.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Cancer ; Computational Biology ; Dynamics ; Glioblastoma ; Immunology ; Immunotherapy ; Single-cell Biology ; Systems Immunology ; Temporal Transcriptomics ; Tumor-associated-macrophages; Tumor-associated Macrophages; Resistant Acid-phosphatase; Nk Cells; Natural-killer; Growth-factor; Rna-seq; Expression; Regulators; Trem2; Polarization
ISSN (print) / ISBN
0092-8674
e-ISSN
1097-4172
Journal
Cell
Quellenangaben
Volume: 187,
Issue: 1,
Pages: 149-165.e23
Publisher
Cell Press
Publishing Place
Cambridge, Mass.
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Computational Biology (ICB)
Grants
Azrieli Graduate Fellowship - Fulbright Scholarship
EMBO postdoctoral fellowship
postdoctoral fellowship of the Swiss Friends of the Weizmann Institute of Science and of the Azrieli Foundation - Koshland award
EMBO postdoctoral fellowship
postdoctoral fellowship of the Swiss Friends of the Weizmann Institute of Science and of the Azrieli Foundation - Koshland award