Riegel, Dania and Romero-Fernandez, Elena and Simon, Malte and Adenugba, Akinbami Raphael and Singer, Katrin and Mayr, Roman and Weber, Florian and Kleemann, Mark and Imbusch, Charles D. and Kreutz, Marina and Brors, Benedikt and Ugele, Ines and Werner, Jens M. and Siska, Peter J. and Schmidl, Christian (2023) Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+T cells. MOLECULAR CELL, 83 (4). 622-+. ISSN 1097-2765, 1097-4164
Full text not available from this repository. (Request a copy)Abstract
Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring under-lying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify gene-regulatory landscapes in a wide breadth of functional and dysfunctional CD8+ TIL states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with sin-gle-cell RNA-seq data from tumor-entity-matching samples and prioritize cell-state-specific genes by super-enhancer analysis. Besides revealing entity-specific chromatin remodeling in exhausted TILs, our an-alyses identify a common chromatin trajectory to TIL dysfunction and determine key enhancers, transcrip-tional regulators, and deregulated genes involved in this process. Finally, we validate enhancer regulation at immunotherapeutically relevant loci by targeting non-coding regulatory elements with potent CRISPR ac-tivators and repressors. In summary, our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor-infiltrating lymphocytes.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CD8(+) T-CELLS; REGULATORY ELEMENTS; CHROMATIN; IMMUNOTHERAPY; ALIGNMENT; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Unfallchirurgie Medicine > Lehrstuhl für Hals-Nasen-Ohren-Heilkunde Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 09:21 |
| Last Modified: | 30 Jan 2024 09:21 |
| URI: | https://pred.uni-regensburg.de/id/eprint/59391 |
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