Zman-seq: Time-resolved single cell transcriptomics reveals immune trajectories in glioblastoma
You are cordially invited to a special seminar of the Department of Human molecular Genetics and Biochemistry Faculty of Medicine
By: Daniel Kirschenbaum Ph.D.
Department of Immunology, Weizmann Institute of Science
Title:
Zman-seq: Time-resolved single cell transcriptomics reveals immune trajectories in glioblastoma
:Abstract
: Immune cells sense their environment and respond by reprograming their functional state. Deciphering the cellular trajectories underlying immune adaptation in diverse pathological sites as they unfold across time, is fundamental for advancing biology. Empirical in vivo genomic technologies that capture cellular dynamics by measuring both cell state and time are currently lacking. Here, we present Zman-seq, a single-cell technology that tracks transcriptomic dynamics across time by introducing fluorescent antibody time stamps into immune cells in circulation and tracking them in tissues hours to days later. We applied Zman-seq to resolve immune cell state-transition trajectories of the notoriously dysfunctional immune microenvironment of glioblastoma (GBM), a hard-to-treat lethal brain tumor. By measuring the exposure time of infiltrating immune cells to the tumor microenvironment, Zman-seq defines the cellular trajectory and differentiation pathways underlying immune incompetence in GBM. We found that within 24 hours of tumor infiltration, cytotoxic NK cells rapidly transitioned to a dysfunctional NK cell program regulated by TGF-β signaling, while infiltrating monocytes differentiated into immunosuppressive macrophages, characterized by upregulation of key suppressive myeloid checkpoints such as Trem2, Il18bp and Arg1, over 36 to 48 hours. Treatment of GBM-bearing mice with anti-TREM2 antagonistic antibody reshaped the tumor microenvironment by redirecting the monocyte-to-macrophage trajectory from monocytes to pro-inflammatory macrophages. Zman-seq is a broadly applicable technology enabling empirical measurements of differentiation trajectories, which may enhance the development of precise and more efficacious immunotherapies.
The Seminar will take place on Sunday, December 24, 2023 at 10:15
At the Faculty of Medicine Building, Room 119
