TY  - JOUR
AU  - Riegel, Dania
AU  - Romero-Fernández, Elena
AU  - Simon, Malte
AU  - Adenugba, Akinbami Raphael
AU  - Singer, Katrin
AU  - Mayr, Roman
AU  - Weber, Florian
AU  - Kleemann, Mark
AU  - Imbusch, Charles D
AU  - Kreutz, Marina
AU  - Brors, Benedikt
AU  - Ugele, Ines
AU  - Werner, Jens M
AU  - Siska, Peter J
AU  - Schmidl, Christian
TI  - Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells.
JO  - Molecular cell
VL  - 83
IS  - 4
SN  - 1097-2765
CY  - New York, NY
PB  - Elsevier
M1  - DKFZ-2023-00123
SP  - 622-636.e10.
PY  - 2023
N1  - #EA:B330# / 83(4), pp. 622-636.e10. 2023
AB  - Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying 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 single-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 analyses identify a common chromatin trajectory to TIL dysfunction and determine key enhancers, transcriptional 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 activators and repressors. In summary, our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor-infiltrating lymphocytes.
KW  - CRISPR activation (Other)
KW  - CRISPR interference (Other)
KW  - T cell exhaustion (Other)
KW  - cancer immunology (Other)
KW  - chromatin accessibility (Other)
KW  - enhancer (Other)
KW  - gene regulation (Other)
KW  - single-cell ATAC-seq (Other)
KW  - tumor-infiltrating T cells (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36657444
DO  - DOI:10.1016/j.molcel.2022.12.029
UR  - https://inrepo02.dkfz.de/record/210399
ER  -